Substituted 1 H-Pyrrolo [2, 3-b] pyridine and 1 H-Pyrazolo [3, 4-b] pyridine Derivatives as Salt Inducible Kinase 2 (SIK2) Inhibitors

ABSTRACT

Compounds according to Formulas I, IA or IB: 
     
       
         
         
             
             
         
       
     
     to pharmaceutically acceptable composition, salts thereof, their synthesis and their use as SIK2 inhibitors including such compounds and methods of using said compounds in the treatment of various diseases and/or disorders such as cancer, stroke, cardiovascular, obesity and type II diabetes.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 14/101,109 filed Dec. 9, 2013, the entirety of which isincorporated by reference herein, and claims the benefit of U.S. PatentApplication No. 61/737,618 filed Dec. 14, 2012.

INCORPORATION BY REFERENCE

The sequence listing (“Sequence Listing”) submitted in ASCII text filedin connection with this application, created Nov. 9, 2015, 231 KB, isincorporated herein by reference.

FIELD OF INVENTION

The present invention is directed to compounds, their synthesis, andtheir use as modulators or inhibitors of the Salt Inducible Kinase 2(“SIK2” kinase)(SEQ ID NO: 11). The compounds of the present inventionare useful for modulating (e.g. inhibiting) SIK2 (SEQ ID NO: 11)activity and for treating diseases or conditions mediated by SIK2 (SEQID NO: 11) such as for example, disease states associated with abnormalcell growth such as cancer, stroke, obesity and type 2 diabetes.

BACKGROUND OF THE INVENTION

Substituted 5-(pyrazin-2-yl)-1 h-pyrazolo[3,4-b]pyridine andpyrazolo[3,4-b]pyridine derivatives as protein kinase inhibitors aredescribed in US Patent Publication No. 2013/0102586 and InternationalPublication No. WO2012/135631.

Salt Inducible Kinase 2 (SIK2)(SEQ ID NO: 11) is a centrosome kinaserequired for bipolar mitotic spindle formation and is a Ser/Thr kinase.Three isoforms of SIK family have been reported; SIK1 (SNF1LK)(SEQ IDNO: 10), SIK2 (SNF1LK, QIK)(SEQ ID NO: 11) and SIK3 (QSK)(SEQ ID NO:24). The SIK2 (SEQ ID NO: 11) is amplified in large B-cell lymphoma,ovarian, melanoma and beast cancer patients. Recent findings suggestthat SIK2 (SEQ ID NO: 11) over expression enhanced cell death afterischemia and metabolic diseases as well. Inhibition of SIK2 (SEQ ID NO:11) was reported to cause SIK2-dependent centrosome splitting ininterphase while SIK2 (SEQ ID NO: 11) depletion blocked centrosomeseparation in mitosis, sensitizing ovarian cancers to paclitaxel inculture and in xenografts. Depletion of SIK2 (SEQ ID NO: 11) alsodelayed G1/S transition and reduced AKT phosphorylation. Higherexpression of SIK2 (SEQ ID NO: 11) significantly correlated with poorsurvival in patients with high-grade serous ovarian cancers (Bast, Jr.,et al., Cancer Cell., 18, 109-121, 2010) and is a plausible therapeutictarget for therapy in ovarian cancers.

The Salt Inducible Kinase 2 (SIK2) (SEQ ID NO: 11) depletion in cancercells had a significant decrease in cancer cell growth, delayed mitoticprogression and G1/S transition and decreased AKT phosphorylation.Deficiency of SIK2 (SEQ ID NO: 11) significantly sensitized cancer cellsto taxnae and paclitaxel in vivo xenograft models in interfering withmitotic progression. In this work we established the basis of utilizingSIK2 (SEQ ID NO: 11) as a target for therapy in cancer by evaluating itseffect on taxane, paclitaxel sensitization in a panel of cell lines,confirming activity in xenografts that the SIK2 (SEQ ID NO: 11) isover-expressed in 30% of ovarian cancers and to further develop an assayto measure SIK2 (SEQ ID NO: 11) activity. Ovarian Cancer (OC) accounts3% of cancers in women and is the fifth leading cause of cancer relateddeath among women. Nearly 22,240 women were diagnosed in 2013 with OC inUS alone with about 14,030 women estimated to die from this deadlygynecologic malignancy of American women. Ovarian cancer is one of thecancers difficult to detect prior to its advanced stage. The currentlyavailable treatments, other than surgery and radiation, arechemotheurapeutics and the few approved targeted agents.

Additionally, an advantage of SIK2 (SEQ ID NO: 11) inhibitors that blockSIK2 (SEQ ID NO: 11) activity is to recruit melanogenesis. This leads torecovery of brown hair in 6 to 8 weeks.

Recent reports suggests that the over expression of SIK2 (SEQ ID NO: 11)controlled the TORC1 (Transducer of regulated CREB activity-1) fromentering the nucleus and activating CREB, and this enhanced cell deathafter ischemia. The SIK2 (SEQ ID NO: 11) inhibitor could enhance CREB(cAMP Responsive Element-Binding) protein activity and prevent neurondeath in response to ischemia. The SIK2 (SEQ ID NO: 11) deficient micewere protected from stroke suggests that SIK2 degradation after ischemiais required for neurons.

There continues to be a need for new drugs to treat multiple cancerindications, melanogenesis, stroke, cardiovascular, obesity and type IIdiabetes diseases where SIK2 (SEQ ID NO: 11) and its isoforms play apivotal role in these multiple disease indications. Using the homologystructure of the SIK2 (SEQ ID NO: 11) and our FFDD (Fragment Field DrugDesign) or FIELDS guided lead identification, screening and SAR efforts;we have discovered the first-in-class novel H-pyrrolo[2,3-b]pyridine and1H-pyrazolo[3,4-b]pyridine inhibitors of SIK2 (SEQ ID NO: 11) that wouldbe useful for treating multiple disease indications, including cancer(ovarian, breast, prostate, diffuse large B-cell lymphoma and melanoma),stroke, obesity, type II diabetes. We disclose here the composition andmethod of use for inhibitors of SIK2 (SEQ ID NO: 11).

Accordingly, the present invention is directed to composition and methodof use for novel H-pyrrolo[2,3-b]pyridine and 1H-pyrazolo[3,4-b]pyridineinhibitors of SIK2 (SEQ ID NO: 11) and SIK3 (SEQ ID NO: 24) useful fortreating multiple disease indications, including cancer (ovarian,breast, prostate, diffuse large B-cell lymphoma, lung, NSCL andmelanoma), autophagy function, stroke, obesity, and type II diabetes.

SUMMARY OF THE INVENTION

The present invention concerns compounds active on protein kinases,specifically SIK1 (SEQ ID NO: 10), SIK2 (SEQ ID NO: 11) and SIK3 (SEQ IDNO: 24), and in general, including but not limited to CLK1 (SEQ ID NO:1), CLK2 (SEQ ID NO: 2), DYRK1 (SEQ ID NO: 13), DYRK1A (SEQ ID NO: 3),ITK (SEQ ID NO: 14), Janus family of kinases (JAK1 (SEQ ID NO: 4), JAK2(SEQ ID NO: 5), JAK3 (SEQ ID NO: 6) and TYK2 (SEQ ID NO: 15)), LRRK2(SEQ ID NO: 12), LRRK2 G2019 (SEQ ID NO: 7), MELK (SEQ ID NO: 8), MAP4K1(SEQ ID NO: 16), MAP4K5 (SEQ ID NO: 9), NIK (SEQ ID NO: 17), PKCd (SEQID NO: 18), RSK4 (SEQ ID NO: 19), STK2 (SEQ ID NO: 20), STK3 (SEQ ID NO:21), STK4 (SEQ ID NO: 22), STK10 (SEQ ID NO: 23) and TNIK1 (SEQ ID NO:28), including any mutations of these kinases and the use thereof intreating disease and conditions associated with egulations of theactivity of these kianses. More specifically the invention concernscompounds of Formula I, IA, and IB as described below. Thus theinvention provides novel use of compounds for therapeutic methodsinvolving inhibition and or modulation of protein kinases specificallySIK family of kinases; SIK1 (SNF1LK)(SEQ ID NO: 10), SIK2 (SNF1LK,QIK)(SEQ ID NO: 11) and SIK3 (QSK)(SEQ ID NO: 24), as well as novelcompounds that can be used for the therapeutic methods involvingmodulation of these protein kinases.

The present invention relates to compounds according to Formulas I, IAor IB:

to pharmaceutically acceptable composition, salts thereof, theirsynthesis and their use as SIK2 inhibitors including such compounds andmethods of their use in the treatment of various diseases and disorderssuch as cancer, stroke, obesity and type II diabetes.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1: shows two panels of SIK2 (SEQ ID NO: 11) inhibitor examples:Panel A on the left: 135 (▪), 142 (Δ) and Panel B on the right: 133 (▪)and 168 (Δ). The percent activity is plotted against log M.

FIG. 2: shows SIK2 inhibitor examples tested in SK-OV-3 cell lines onthe left Panel A and OVCAR3 cell lines on the right Panel B withCisplatin as control. The survival fraction is plotted against theconcentration.

FIG. 2b 1: Effects of four 1H-Pyrrolo[2,3-b]pyridine and1H-Pyrazolo[3,4-b]pyridine derivatives on the SIK2-expressed SKOv3cells.

FIG. 2b 2: Effects of four 1H-Pyrrolo[2,3-b]pyridine and1H-Pyrazolo[3,4-b]pyridine derivatives on the SIK2-expressed OVCAR3cells.

FIG. 2b 3: Effects of four 1H-Pyrrolo[2,3-b]pyridine and1H-Pyrazolo[3,4-b]pyridine derivatives on the SIK2-expressed ES-2 cells.

FIG. 3: depicts the structure based sequence alignment in Clustal W ofthe catalytic protein kinase domains of SIK1 (SNF1LK)(SEQ ID NO: 10),SIK2 (SNF1LK, QIK)(SEQ ID NO: 11), SIK3 (QSK)(SEQ ID NO: 24), AMPK (SEQID NO: 27) and MARK2 (SEQ ID NO: 25). Amino acid residue annotation wereidentical residues (*), highly conserved residues (:), and similarresidues (.) The active site residues highlighted in yellow and thegatekeeper residues in turquoise and the DFG residues shown in yellow.

FIG. 4: Homology model of SIK2 (SEQ ID NO: 11) in complex with one ofthe lead inhibitor. The critical active site residues shown incolor-by-atom in stick representations. The inhibitor binding sitedepicted in surface in complex with SIK2 (SEQ ID NO: 11). Compoundbelongs to 1H-pyrrolo[2,3-b]pyridine structural class claimed.

FIG. 5a-c : Plots of tumor volume, weight, and number against a control,two 1H-Pyrrolo[2,3-b]pyridine compounds, taxol, and a combination. Thedata show that the compounds of the present invention and taxol havesignificant antitumor effects and as a single agent these seriesdissemination of tumor cell in vivo.

BRIEF DESCRIPTION OF THE SEQUENCES

SEQ ID NO: 1 is the human CLK1 protein kinase sequence;

SEQ ID NO: 2 is the human CLK2 protein kinase sequence;

SEQ ID NO: 3 is the human DYRK1A protein kinase sequence;

SEQ ID NO: 4 is the human JAK1 protein kinase sequence;

SEQ ID NO: 5 is the human JAK2 protein kinase sequence;

SEQ ID NO: 6 is the human JAK3 protein kinase sequence;

SEQ ID NO: 7 is the human LRRK2 G2019 protein kinase sequence;

SEQ ID NO: 8 is the human MELK protein kinase sequence;

SEQ ID NO: 9 is the human MAP4K5 protein kinase sequence;

SEQ ID NO: 10 is the human SIK1 protein kinase sequence;

SEQ ID NO: 11 is the human SIK2 protein kinase sequence;

SEQ ID NO: 12 is the human LRRK2 protein kinase sequence;

SEQ ID NO: 13 is the human DYRK1 protein kinase sequence;

SEQ ID NO: 14 is the human ITK protein kinase sequence;

SEQ ID NO: 15 is the human TYK2 protein kinase sequence;

SEQ ID NO: 16 is the human MAP4K1 protein kinase sequence;

SEQ ID NO: 17 is the human NIK protein kinase sequence;

SEQ ID NO: 18 is the human PKC-delta protein kinase sequence;

SEQ ID NO: 19 is the human RSK4 protein kinase sequence

SEQ ID NO: 20 is the human NEK4 protein kinase sequence;

SEQ ID NO: 21 is the human STK3 protein kinase sequence;

SEQ ID NO: 22 is the human STK4 protein kinase sequence;

SEQ ID NO: 23 is the human STK10 protein kinase sequence;

SEQ ID NO: 24 is the human SIK3 protein kinase sequence;

SEQ ID NO: 25 is the human MARK2 protein kinase sequence;

SEQ ID NO: 26 is the human STK11 protein kinase sequence;

SEQ ID NO: 27 is the human AMPK protein kinase sequence; and

SEQ ID NO: 28 is the human TNIK protein kinase sequence.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of the present invention are described by the Formulas I, IAor IB:

or a pharmaceutically acceptable salt thereof, wherein:

X is N or CH; L¹ is H, F; or

L¹ is thienyl, phenyl, pyrrolyl, pyridyl,

piperazinyl,

any of which is optionally substituted with 1-3 substituents, eachsubstituent independently selected from halo, C₁₋₄alkyl, C₁₋₄alkoxy,trifluoromethyl, trifluoromethoxy, piperazinyl, methylpiperazinyl,

Q is a direct bond, thienyl, thiazolyl, phenyl,

furanyl, piperazinyl, or pyrazolyl;R¹ is each H, halo, —CN, C₁₋₄alkyl, C₁₋₄alkoxy,

Z is a direct bond, thienyl, thiazolyl, phenyl,

furanyl, piperazinyl, or pyrazolyl;R² is each independently H, halo, —CN, C₁₋₄alkyl, C₁₋₄alkoxy,

-   -   n is 0, 1, or 2; and    -   m is 0, 1, or 2;    -   provided that the compound is not a compound selected from the        following list (“Exclusion List”):

and further provided that at least one of L¹, R¹, and R² is not H.

In an aspect of the invention, compounds of the present invention aredescribed by Formula (IA) and pharmaceutically acceptable salts thereof,wherein X is CH; and the other variables are as defined above forFormula (IA), provided that the compound is not one in the ExclusionList and at least one of L¹, R¹, and R² is not H.

In one embodiment of this aspect, compounds of the present invention aredescribed by Formula (IA) and pharmaceutically acceptable salts thereof,wherein X is CH; L¹ is H or F; and the other variables are as definedabove for Formula (IA), provided that the compound is not one in theExclusion List and at least one of R¹ and R² is not H.

In another embodiment of this aspect, compounds of the present inventionare described by Formula (IA) and pharmaceutically acceptable saltsthereof, wherein X is CH; L¹ is thienyl optionally substituted with 1-3substituents, each substituent independently selected from halo,C₁₋₄alkyl, C₁₋₄alkoxy, trifluoromethyl, trifluoromethoxy, piperazinyl,methylpiperazinyl,

and the other variables are as defined above for Formula (IA), providedthat the compound is not one in the Exclusion List.

In still another embodiment of this aspect, compounds of the presentinvention are described by Formula (IA) and pharmaceutically acceptablesalts thereof, wherein X is CH; L¹ is phenyl optionally substituted with1-3 substituents, each substituent independently selected from halo,C₁₋₄alkyl, C₁₋₄alkoxy, trifluoromethyl, trifluoromethoxy, piperazinyl,methylpiperazinyl,

and the other variables are as defined above for Formula (IA), providedthat the compound is not one in the Exclusion List.

In yet another embodiment of this aspect, compounds of the presentinvention are described by Formula (IA) and pharmaceutically acceptablesalts thereof, wherein X is CH; L¹ is pyrrolyl optionally substitutedwith 1-3 substituents, each substituent independently selected fromhalo, C₁₋₄alkyl, C₁₋₄alkoxy, trifluoromethyl, trifluoromethoxy,piperazinyl, methylpiperazinyl,

and the other variables are as defined above for Formula (IA), providedthat the compound is not one in the Exclusion List.

In still another embodiment of this aspect, compounds of the presentinvention are described by Formula (IA) and pharmaceutically acceptablesalts thereof, wherein X is CH; L¹ is pyridyl optionally substitutedwith 1-3 substituents, each substituent independently selected fromhalo, C₁₋₄alkyl, C₁₋₄alkoxy, trifluoromethyl, trifluoromethoxy,piperazinyl, methylpiperazinyl,

and the other variables are as defined above for Formula (IA), providedthat the compound is not one in the Exclusion List.

In another embodiment of this aspect, compounds of the present inventionare described by Formula (IA) and pharmaceutically acceptable saltsthereof, wherein X is CH; L¹ is

optionally substituted with 1-3 substituents, each substituentindependently selected from halo, C₁₋₄alkyl, C₁₋₄alkoxy,trifluoromethyl, trifluoromethoxy, piperazinyl, methylpiperazinyl,

and the other variables are as defined above for Formula (IA), providedthat the compound is not one in the Exclusion List.

In yet another embodiment of this aspect, compounds of the presentinvention are described by Formula (IA) and pharmaceutically acceptablesalts thereof, wherein X is CH; L¹ is piperazinyl optionally substitutedwith 1-3 substituents, each substituent independently selected fromhalo, C₁₋₄alkyl, C₁₋₄alkoxy, trifluoromethyl, trifluoromethoxy,piperazinyl, methylpiperazinyl,

and the other variables are as defined above for Formula (IA), providedthat the compound is not one in the Exclusion List.

In another embodiment of this aspect, compounds of the present inventionare described by Formula (IA) and pharmaceutically acceptable saltsthereof, wherein X is CH; L¹ is

optionally substituted with 1-3 substituents, each substituentindependently selected from halo, C₁₋₄alkyl, C₁₋₄alkoxy,trifluoromethyl, trifluoromethoxy, piperazinyl, methylpiperazinyl,

and the other variables are as defined above for Formula (IA), providedthat the compound is not one in the Exclusion List.

In another embodiment of this aspect, compounds of the present inventionare described by Formula (IA) and pharmaceutically acceptable saltsthereof, wherein X is CH; L¹ is

optionally substituted with 1-3 substituents, each substituentindependently selected from halo, C₁₋₄alkyl, C₁₋₄alkoxy,trifluoromethyl, trifluoromethoxy, piperazinyl, methylpiperazinyl,

and the other variables are as defined above for Formula (IA), providedthat the compound is not one in the Exclusion List.

In an aspect of the invention, compounds of the present invention aredescribed by Formula (IA) and pharmaceutically acceptable salts thereof,wherein X is N; and the other variables are as defined above for Formula(IA), provided that the compound is not one in the Exclusion List and atleast one of L¹, R¹, and R² is not H.

In one embodiment of this aspect, compounds of the present invention aredescribed by Formula (IA) and pharmaceutically acceptable salts thereof,wherein X is N; L¹ is H or F; and the other variables are as definedabove for Formula (IA), provided that the compound is not one in theExclusion List and at least one of R¹ and R² is not H.

In another embodiment of this aspect, compounds of the present inventionare described by Formula (IA) and pharmaceutically acceptable saltsthereof, wherein X is N; L¹ is thienyl optionally substituted with 1-3substituents, each substituent independently selected from halo,C₁₋₄alkyl, C₁₋₄alkoxy, trifluoromethyl, trifluoromethoxy, piperazinyl,methylpiperazinyl,

and the other variables are as defined above for Formula (IA), providedthat the compound is not one in the Exclusion List.

In still another embodiment of this aspect, compounds of the presentinvention are described by Formula (IA) and pharmaceutically acceptablesalts thereof, wherein X is N; L¹ is phenyl optionally substituted with1-3 substituents, each substituent independently selected from halo,C₁₋₄alkyl, C₁₋₄alkoxy, trifluoromethyl, trifluoromethoxy, piperazinyl,methylpiperazinyl,

and the other variables are as defined above for Formula (IA), providedthat the compound is not one in the Exclusion List.

In yet another embodiment of this aspect, compounds of the presentinvention are described by Formula (IA) and pharmaceutically acceptablesalts thereof, wherein X is N; L¹ is pyrrolyl optionally substitutedwith 1-3 substituents, each substituent independently selected fromhalo, C₁₋₄alkyl, C₁₋₄alkoxy, trifluoromethyl, trifluoromethoxy,piperazinyl, methylpiperazinyl,

and the other variables are as defined above for Formula (IA), providedthat the compound is not one in the Exclusion List.

In still another embodiment of this aspect, compounds of the presentinvention are described by Formula (IA) and pharmaceutically acceptablesalts thereof, wherein X is N; L¹ is pyridyl optionally substituted with1-3 substituents, each substituent independently selected from halo,C₁₋₄alkyl, C₁₋₄alkoxy, trifluoromethyl, trifluoromethoxy, piperazinyl,methylpiperazinyl,

and the other variables are as defined above for Formula (IA), providedthat the compound is not one in the Exclusion List.

In another embodiment of this aspect, compounds of the present inventionare described by Formula (IA) and pharmaceutically acceptable saltsthereof, wherein X is N; L¹ is

optionally substituted with 1-3 substituents, each substituentindependently selected from halo, C₁₋₄alkyl, C₁₋₄alkoxy,trifluoromethyl, trifluoromethoxy, piperazinyl, methylpiperazinyl,

and the other variables are as defined above for Formula (IA), providedthat the compound is not one in the Exclusion List.

In yet another embodiment of this aspect, compounds of the presentinvention are described by Formula (IA) and pharmaceutically acceptablesalts thereof, wherein X is N; L¹ is piperazinyl optionally substitutedwith 1-3 substituents, each substituent independently selected fromhalo, C₁₋₄alkyl, C₁₋₄alkoxy, trifluoromethyl, trifluoromethoxy,piperazinyl, methylpiperazinyl,

and the other variables are as defined above for Formula (IA), providedthat the compound is not one in the Exclusion List.

In another embodiment of this aspect, compounds of the present inventionare described by Formula (IA) and pharmaceutically acceptable saltsthereof, wherein X is N; L¹ is

optionally substituted with 1-3 substituents, each substituentindependently selected from halo, C₁₋₄alkyl, C₁₋₄alkoxy,trifluoromethyl, trifluoromethoxy, piperazinyl, methylpiperazinyl,

and the other variables are as defined above for Formula (IA), providedthat the compound is not one in the Exclusion List.

In another embodiment of this aspect, compounds of the present inventionare described by Formula (IA) and pharmaceutically acceptable saltsthereof, wherein X is N; L¹ is

optionally substituted with 1-3 substituents, each substituentindependently selected from halo, C₁₋₄alkyl, C₁₋₄alkoxy,trifluoromethyl, trifluoromethoxy, piperazinyl, methylpiperazinyl,

and the other variables are as defined above for Formula (IA), providedthat the compound is not one in the Exclusion List.

In an aspect of the invention, compounds of the present invention aredescribed by Formula (IB) and pharmaceutically acceptable salts thereof,wherein X is CH; and the other variables are as defined above forFormula (TB), provided that the compound is not one in the ExclusionList and at least one of L¹, R¹, and R² is not H.

In one embodiment of this aspect, compounds of the present invention aredescribed by Formula (IB) and pharmaceutically acceptable salts thereof,wherein X is CH; L¹ is H or F; and the other variables are as definedabove for Formula (TB), provided that the compound is not one in theExclusion List and at least one of R¹ and R² is not H.

In another embodiment of this aspect, compounds of the present inventionare described by Formula (IB) and pharmaceutically acceptable saltsthereof, wherein X is CH; L¹ is thienyl optionally substituted with 1-3substituents, each substituent independently selected from halo,C₁₋₄alkyl, C₁₋₄alkoxy, trifluoromethyl, trifluoromethoxy, piperazinyl,methylpiperazinyl,

and the other variables are as defined above for Formula (TB), providedthat the compound is not one in the Exclusion List.

In still another embodiment of this aspect, compounds of the presentinvention are described by Formula (IB) and pharmaceutically acceptablesalts thereof, wherein X is CH; L¹ is phenyl optionally substituted with1-3 substituents, each substituent independently selected from halo,C₁₋₄alkyl, C₁₋₄alkoxy, trifluoromethyl, trifluoromethoxy, piperazinyl,methylpiperazinyl,

and the other variables are as defined above for Formula (IB), providedthat the compound is not one in the Exclusion List.

In yet another embodiment of this aspect, compounds of the presentinvention are described by Formula (IB) and pharmaceutically acceptablesalts thereof, wherein X is CH; L¹ is pyrrolyl optionally substitutedwith 1-3 substituents, each substituent independently selected fromhalo, C₁₋₄alkyl, C₁₋₄alkoxy, trifluoromethyl, trifluoromethoxy,piperazinyl, methylpiperazinyl,

and the other variables are as defined above for Formula (TB), providedthat the compound is not one in the Exclusion List.

In still another embodiment of this aspect, compounds of the presentinvention are described by Formula (IB) and pharmaceutically acceptablesalts thereof, wherein X is CH; L¹ is pyridyl optionally substitutedwith 1-3 substituents, each substituent independently selected fromhalo, C₁₋₄alkyl, C₁₋₄alkoxy, trifluoromethyl, trifluoromethoxy,piperazinyl, methylpiperazinyl,

and the other variables are as defined above for Formula (TB), providedthat the compound is not one in the Exclusion List.

In another embodiment of this aspect, compounds of the present inventionare described by Formula (IB) and pharmaceutically acceptable saltsthereof, wherein X is CH; L¹ is

optionally substituted with 1-3 substituents, each substituentindependently selected from halo, C₁₋₄alkyl, C₁₋₄alkoxy,trifluoromethyl, trifluoromethoxy, piperazinyl, methylpiperazinyl,

and the other variables are as defined above for Formula (IB), providedthat the compound is not one in the Exclusion List.

In yet another embodiment of this aspect, compounds of the presentinvention are described by Formula (IB) and pharmaceutically acceptablesalts thereof, wherein X is CH; L¹ is piperazinyl optionally substitutedwith 1-3 substituents, each substituent independently selected fromhalo, C₁₋₄alkyl, C₁₋₄alkoxy, trifluoromethyl, trifluoromethoxy,piperazinyl, methylpiperazinyl,

and the other variables are as defined above for Formula (IB), providedthat the compound is not one in the Exclusion List.

In another embodiment of this aspect, compounds of the present inventionare described by Formula (IB) and pharmaceutically acceptable saltsthereof, wherein X is CH; L¹ is

optionally substituted with 1-3 substituents, each substituentindependently selected from halo, C₁₋₄alkyl, C₁₋₄alkoxy,trifluoromethyl, trifluoromethoxy, piperazinyl, methylpiperazinyl,

and the other variables are as defined above for Formula (IA), providedthat the compound is not one in the Exclusion List.

In another embodiment of this aspect, compounds of the present inventionare described by Formula (IB) and pharmaceutically acceptable saltsthereof, wherein X is CH; L¹ is

optionally substituted with 1-3 substituents, each substituentindependently selected from halo, C₁₋₄alkyl, C₁₋₄alkoxy,trifluoromethyl, trifluoromethoxy, piperazinyl, methylpiperazinyl,

and the other variables are as defined above for Formula (IB), providedthat the compound is not one in the Exclusion List.

Compounds of the present invention include:

Other compounds of the present invention include:

Other compounds of the present invention include:

In an aspect, the present invention is a method of treating cancer orhyperproliferative disorders by administering an effective amount of acompound according to Formulas I, IA or IB:

or a pharmaceutically acceptable salt thereof, wherein:

-   X is N or CH;-   L¹ is H, F; or-   L¹ is thienyl, phenyl, pyrrolyl, pyridyl,

piperazinyl,

any of which is optionally substituted with 1-3 substituents, eachsubstituent independently selected from halo, C₁₋₄alkyl, C₁₋₄alkoxy,trifluoromethyl, trifluoromethoxy, piperazinyl, methylpiperazinyl,

-   Q is a direct bond, thienyl, thiazolyl, phenyl,

furanyl, or piperazinyl;

-   R¹ is each independently H, halo, —CN, C₁₋₄alkyl, C₁₋₄alkoxy,

-   Z is a direct bond, thienyl, thiazolyl, phenyl,

furanyl, or piperazinyl;

-   R² is each independently H, halo, —CN, C₁₋₄alkyl, C₁₋₄alkoxy,

-   n is 0, 1, or 2; and-   m is 0, 1, or 2;-   provided that at least one of L¹, R¹, and R² is not H

In an embodiment of the aspect, the cancer is of colon, breast, stomach,prostate, pancreas, or ovarian tissue.

In another embodiment of the aspect, the cancer or hyperproliferativedisorder is lung cancer, NSCLC (non small cell lung cancer), oat-cellcancer, bone cancer, pancreatic cancer, skin cancer, dermatofibrosarcomaprotuberans, cancer of the head and neck, cutaneous or intraocularmelanoma, uterine cancer, ovarian cancer, colo-rectal cancer, cancer ofthe anal region, stomach cancer, colon cancer, breast cancer,gynecologic tumors (e.g., uterine sarcomas, carcinoma of the fallopiantubes, carcinoma of the endometrium, carcinoma of the cervix, carcinomaof the vagina or carcinoma of the vulva), Hodgkin's Disease,hepatocellular cancer, cancer of the esophagus, cancer of the smallintestine, cancer of the endocrine system (e.g., cancer of the thyroid,pancreas, parathyroid or adrenal glands), sarcomas of soft tissues,cancer of the urethra, cancer of the penis, prostate cancer(particularly hormone-refractory), chronic or acute leukemia, solidtumors of childhood, hypereosinophilia, lymphocytic lymphomas, cancer ofthe bladder, cancer of the kidney or ureter, renal cell carcinoma,carcinoma of the renal pelvis, pediatric malignancy, neoplasms of thecentral nervous system, primary CNS lymphoma, spinal axis tumors,medulloblastoma, brain stem gliomas, pituitary adenomas, Barrett'sesophagus, pre-malignant syndrome, neoplastic cutaneous disease,psoriasis, mycoses fungoides, benign prostatic hypertrophy, diabeticretinopathy, retinal ischemia, and retinal neovascularization, hepaticcirrhosis, angiogenesis, cardiovascular disease, atherosclerosis,immunological disease, autoimmune disease, or renal.

These and other aspects of the invention will be apparent upon referenceto the following detailed description. To that end, certain patent andother documents are cited herein to more specifically set forth variousaspects of this invention. Each of these documents is herebyincorporated by reference in its entirety.

Unless otherwise stated the following terms used in the specificationand claims have the meanings discussed below:

“Alkyl” refers to a saturated straight or branched hydrocarbon radicalof one to six carbon atoms, preferably one to four carbon atoms, e.g.,methyl, ethyl, propyl, 2-propyl, n-butyl, iso-butyl, tert-butyl, pentyl,hexyl, and the like, preferably methyl, ethyl, propyl, or 2-propyl.Representative saturated straight chain alkyls include methyl, ethyl,n-propyl, n-butyl, n-pentyl, n-hexyl, and the like; while saturatedbranched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl,isopentyl, and the like. Cyclic alkyls are referred to herein as a“cycloalkyl.”

Unsaturated alkyls contain at least one double or triple bond betweenadjacent carbon atoms (referred to as an “alkenyl” or “alkynyl”,respectively.) Representative straight chain and branched alkenylsinclude ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl,1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl,2,3-dimethyl-2-butenyl, and the like; while representative straightchain and branched alkynyls include acetylenyl, propynyl, 1-butynyl,2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, and the like.

“C₀₋₄alkyl” refers to an alkyl with 0, 1, 2, 3, or 4 carbon atoms.C₀₋₄alkyl with 0 carbon atoms is a hydrogen atom when terminal and is adirect bond when linking.

“Alkylene” means a linear saturated divalent hydrocarbon radical of oneto six carbon atoms or a branched saturated divalent hydrocarbon radicalof three to six carbon atoms, e.g., methylene, ethylene,2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene,and the like, preferably methylene, ethylene, or propylene.

“Cycloalkyl” refers to a saturated cyclic hydrocarbon radical of threeto eight carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl.

“Alkoxy” means a radical —OR_(a) where R_(a) is an alkyl as definedabove, e.g., methoxy, ethoxy, propoxy, butoxy and the like.

“Halo” means fluoro, chloro, bromo, or iodo, preferably fluoro andchloro.

“Haloalkyl” means alkyl substituted with one or more, preferably one,two or three, same or different halo atoms, e.g., —CH₂Cl, —CF₃, —CH₂CF₃,—CH₂CCl₃, and the like.

“Haloalkoxy” means a radical —OR_(b), where R_(b) is an haloalkyl asdefined above, e.g., trifluoromethoxy, trichloroethoxy,2,2-dichloropropoxy, and the like.

“Acyl” means a radical —C(O)R_(c) where R_(c) is hydrogen, alkyl, orhaloalkyl as defined herein, e.g., formyl, acetyl, trifluoroacetyl,butanoyl, and the like.

“Aryl” refers to an all-carbon monocyclic or fused-ring polycyclic(i.e., rings which share adjacent pairs of carbon atoms) groups of 6 to12 carbon atoms having a completely conjugated pi-electron system.Examples, without limitation, of aryl groups are phenyl, naphthyl andanthracenyl. The aryl group may be substituted or unsubstituted. Unlessspecifically stated otherwise, “substituted aryl” refers to the arylgroup being substituted with one or more, more preferably one, two orthree, even more preferably one or two substituents independentlyselected from the group consisting of alkyl (wherein the alkyl may beoptionally substituted with one or two substituents), haloalkyl, halo,hydroxy, alkoxy, mercapto, alkylthio, cyano, acyl, nitro, phenoxy,heteroaryl, heteroaryloxy, haloalkyl, haloalkoxy, carboxy,alkoxycarbonyl, amino, alkylamino dialkylamino, aryl, heteroaryl,carbocycle or heterocycle (wherein the aryl, heteroaryl, carbocycle orheterocycle may be optionally substituted).

“Heteroaryl” refers to a monocyclic or fused ring (i.e., rings whichshare an adjacent pair of atoms) group of 5 to 12 ring atoms containingone, two, three or four ring heteroatoms selected from N, O, or S, theremaining ring atoms being C, and, in addition, having a completelyconjugated pi-electron system. Examples, without limitation, ofunsubstituted heteroaryl groups are pyrrole, furan, thiophene,imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline,isoquinoline, purine, triazole, tetrazole, triazine, and carbazole. Theheteroaryl group may be unsubstituted or substituted, such as, forexample, 5-methylthiazolyl. Unless specifically stated otherwise,“substituted heteroaryl” refers to the heteroaryl group beingsubstituted with one or more, more preferably one, two or three, evenmore preferably one or two substituents independently selected from thegroup consisting of alkyl (wherein the alkyl may be optionallysubstituted with one or two substituents), haloalkyl, halo, hydroxy,alkoxy, mercapto, alkylthio, cyano, acyl, nitro, haloalkyl, haloalkoxy,carboxy, alkoxycarbonyl, amino, alkylamino dialkylamino, aryl,heteroaryl, carbocycle or heterocycle (wherein the aryl, heteroaryl,carbocycle or heterocycle may be optionally substituted).

“Carbocycle” refers to a saturated, unsaturated or aromatic ring systemhaving 3 to 14 ring carbon atoms. The term “carbocycle”, whethersaturated or partially unsaturated, also refers to rings that areoptionally substituted. The term “carbocycle” includes aryl. The term“carbocycle” also includes aliphatic rings that are fused to one or morearomatic or nonaromatic rings, such as in a decahydronaphthyl ortetrahydronaphthyl, where the radical or point of attachment is on thealiphatic ring. The carbocycle group may be substituted orunsubstituted. Unless specifically stated otherwise, “substitutedcarbocyle” refers to the carbocycle group being substituted with one ormore, more preferably one, two or three, even more preferably one or twosubstituents independently selected from the group consisting of alkyl(wherein the alkyl may be optionally substituted with one or twosubstituents), haloalkyl, halo, hydroxy, alkoxy, mercapto, alkylthio,cyano, acyl, nitro, haloalkyl, haloalkoxy, carboxy, alkoxycarbonyl,amino, alkylamino dialkylamino, aryl, heteroaryl, carbocycle orheterocycle (wherein the aryl, heteroaryl, carbocycle or heterocycle maybe optionally substituted).

“Heterocycle” refers to a saturated, unsaturated or aromatic cyclic ringsystem having 3 to 14 ring atoms in which one, two or three ring atomsare heteroatoms selected from N, O, or S(O)_(m) (where m is an integerfrom 0 to 2), the remaining ring atoms being C, where one or two C atomsmay optionally be replaced by a carbonyl group. The term “heterocycle”includes heteroaryl. Unless specifically stated otherwise, “substitutedheterocyclyl” refers to the heterocyclyl ring being substitutedindependently with one or more, preferably one, two, or threesubstituents selected from alkyl (wherein the alkyl may be optionallysubstituted with one or two substituents), haloalkyl, cycloalkylamino,cycloalkylalkyl, cycloalkylaminoalkyl, cycloalkylalkylaminoalkyl,cyanoalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, alkylamino,dialkylamino, hydroxyalkyl, carboxyalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, carbocycle,heterocycle (wherein the aryl, heteroaryl, carbocycle or heterocycle maybe optionally substituted), aralkyl, heteroaralkyl, saturated orunsaturated heterocycloamino, saturated or unsaturatedheterocycloaminoalkyl, and —COR_(d) (where R_(d) is alkyl). Morespecifically the term heterocyclyl includes, but is not limited to,tetrahydropyranyl, 2,2-dimethyl-1,3-dioxolane, piperidino,N-methylpiperidin-3-yl, piperazino, N-methylpyrrolidin-3-yl,pyrrolidino, morpholino, 4-cyclopropylmethylpiperazino, thiomorpholino,thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide,4-ethyloxycarbonylpiperazino, 3-oxopiperazino, 2-imidazolidone,2-pyrrolidinone, 2-oxohomopiperazino, tetrahydropyrimidin-2-one, and thederivatives thereof, including2-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridinyl. In certainembodiments, the heterocycle group is optionally substituted with one ortwo substituents independently selected from halo, alkyl, alkylsubstituted with carboxy, ester, hydroxy, alkylamino, saturated orunsaturated heterocycloamino, saturated or unsaturatedheterocycloaminoalkyl, or dialkylamino.

“Optional” or “optionally” means that the subsequently described eventor circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “heterocyclic group optionallysubstituted with an alkyl group” means that the alkyl may but need notbe present, and the description includes situations where theheterocycle group is substituted with an alkyl group and situationswhere the heterocycle group is not substituted with the alkyl group.

Lastly, unless specifically stated otherwise, the term “substituted” asused herein means any of the above groups (e.g., alkyl, aryl,heteroaryl, carbocycle, heterocycle, etc.) wherein at least one hydrogenatom is replaced with a substituent. In the case of an oxo substituent(“═O”) two hydrogen atoms are replaced. “Substituents” within thecontext of this invention, if not specified, include halogen, hydroxy,oxo, cyano, nitro, amino, alkylamino, dialkylamino, alkyl, alkoxy,thioalkyl, haloalkyl (e.g., —CF₃), hydroxyalkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, substituted heteroarylalkyl, heterocycle, substitutedheterocycle, heterocyclealkyl, substituted heterocyclealkyl,—NR_(e)R_(f), —NR_(e)C(═O)R_(f), —NR_(e)C(═O)NR_(e)R_(f),—NR_(e)C(═O)OR_(f)—NR_(e)SO₂R_(f), —OR_(e), —C(═O)R_(e)—C(═O)OR_(e),—C(═O)NR_(e)R_(f), —OC(═O)NR_(e)R_(f), —SH, —SR_(e), —SOR_(e),—S(═O)₂R_(e), —OS(═O)₂R_(e), —S(═O)₂OR_(e), wherein R_(e) and R_(f) arethe same or different and independently hydrogen, alkyl, haloalkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,substituted heteroarylalkyl, heterocycle, substituted heterocycle,heterocyclealkyl or substituted heterocyclealkyl.

Compounds that have the same molecular formula but differ in the natureor sequence of bonding of their atoms or the arrangement of their atomsin space are termed “isomers”. Isomers that differ in the arrangement oftheir atoms in space are termed “stereoisomers”. Stereoisomers that arenot mirror images of one another are termed “diastereomers” and thosethat are non-superimposable mirror images of each other are termed“enantiomers”. When a compound has an asymmetric center, for example, itis bonded to four different groups; a pair of enantiomers is possible.An enantiomer can be characterized by the absolute configuration of itsasymmetric center and is described by the R- and S-sequencing rules ofCahn and Prelog (Cahn, R., Ingold, C., and Prelog, V. Angew. Chem.78:413-47, 1966; Angew. Chem. Intemat. Ed. Eng. 5:385-415, 511, 1966),or by the manner in which the molecule rotates the plane of polarizedlight and designated as dextrorotatory or levorotatory (i.e., as (+) or(−)-isomers respectively). A chiral compound can exist as eitherindividual enantiomer or as a mixture thereof. A mixture containingequal proportions of the enantiomers is called a “racemic mixture”.

The compounds of this invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof. Unless indicated otherwise,the description or naming of a particular compound in the specificationand claims is intended to include both individual enantiomers andmixtures, racemic or otherwise, thereof. The methods for thedetermination of stereochemistry and the separation of stereoisomers arewell-known in the art (see discussion in Ch. 4 of ADVANCED ORGANICCHEMISTRY, 4^(th) edition, March, J., John Wiley and Sons, New YorkCity, 1992).

The compounds of the present invention may exhibit the phenomena oftautomerism and structural isomerism. This invention encompasses anytautomeric or structural isomeric form and mixtures thereof whichpossess the ability to modulate SIK2 SEQ ID NO: 11) activity and is notlimited to, any one tautomeric or structural isomeric form.

It is contemplated that a compound of the present invention would bemetabolized by enzymes in the body of the organism such as human beingto generate a metabolite that can modulate the activity of the proteinkinases. Such metabolites are within the scope of the present invention.

A compound of the present invention or a pharmaceutically acceptablesalt thereof can be administered as such to a human patient or can beadministered in pharmaceutical compositions in which the foregoingmaterials are mixed with suitable carriers or excipient(s). Techniquesfor formulation and administration of drugs may be found, for example,in REMINGTON'S PHARMACOLOGICAL SCIENCES, Mack Publishing Co., Easton,Pa., latest edition.

A “pharmaceutical composition” refers to a mixture of one or more of thecompounds described herein or pharmaceutically acceptable salts orprodrugs thereof, with other chemical components, such aspharmaceutically acceptable excipients. The purpose of a pharmaceuticalcomposition is to facilitate administration of a compound to anorganism.

“Pharmaceutically acceptable excipient” refers to an inert substanceadded to a pharmaceutical composition to further facilitateadministration of a compound. Examples, without limitation, ofexcipients include calcium carbonate, calcium phosphate, various sugarsand types of starch, cellulose derivatives, gelatin, vegetable oils andpolyethylene glycols.

“Pharmaceutically acceptable salt” refers to those salts which retainthe biological effectiveness and properties of the parent compound. Suchsalts may include: (1) acid addition salt which is obtained by reactionof the free base of the parent compound with inorganic acids such ashydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid,sulfuric acid, and perchloric acid and the like, or with organic acidssuch as acetic acid, oxalic acid, (D)- or (L)-malic acid, maleic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, tartaric acid, citric acid, succinic acid or malonicacid and the like, preferably hydrochloric acid or (L)-malic acid; or(2) salts formed when an acidic proton present in the parent compoundeither is replaced by a metal ion, e.g., an alkali metal ion, analkaline earth ion, or an aluminum ion; or coordinates with an organicbase such as ethanolamine, diethanolamine, triethanolamine,tromethamine, N-methylglucamine, and the like.

The compound of the present invention may also act, or be designed toact, as a prodrug. A “prodrug” refers to an agent, which is convertedinto the parent drug in vivo. Prodrugs are often useful because, in somesituations, they may be easier to administer than the parent drug. Theymay, for instance, be bioavailable by oral administration whereas theparent drug is not. The prodrug may also have improved solubility inpharmaceutical compositions over the parent drug. An example, withoutlimitation, of a prodrug would be a compound of the present invention,which is, administered as an ester (the “prodrug”), phosphate, amide,carbamate, or urea.

“Therapeutically effective amount” refers to that amount of the compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disorder being treated. In reference to the treatment ofcancer, a therapeutically effective amount refers to that amount whichhas the effect of: (1) reducing the size of the tumor; (2) inhibitingtumor metastasis; (3) inhibiting tumor growth; and/or (4) relieving oneor more symptoms associated with the cancer.

The term “disease”, as used herein, means any disease or otherdeleterious condition in which a SIK2 (SEQ ID NO: 11) is known to play arole. The term “disease” also means those diseases or conditions thatare alleviated by treatment with SIK2 (SEQ ID NO: 11) modulators. Suchconditions include, without limitation, cancer and otherhyperproliferative disorders as well as inflammation. In certainembodiments, the cancer is a cancer of colon, breast, stomach, prostate,pancreas, or ovarian tissue.

The term “SIK2 activity-mediated condition” or “disease”, as usedherein, means any disease or other deleterious condition in which SIK2(SEQ ID NO: 11) activity is known to play a role. The term “SIK2activity-mediated condition” also means those diseases or conditionsthat are alleviated by treatment with a SIK2 (SEQ ID NO: 11) inhibitor.

As used herein, “administer” or “administration” refers to the deliveryof an inventive compound or of a pharmaceutically acceptable saltthereof or of a pharmaceutical composition containing an inventivecompound or a pharmaceutically acceptable salt thereof of this inventionto an organism for the purpose of prevention or treatment of a proteinkinase-related disorder.

Suitable routes of administration may include, without limitation, oral,rectal, transmucosal or intestinal administration or intramuscular,subcutaneous, intramedullary, intrathecal, direct intraventricular,intravenous, intravitreal, intraperitoneal, intranasal, or intraocularinjections. In certain embodiments, the preferred routes ofadministration are oral and intravenous. Alternatively, one mayadminister the compound in a local rather than systemic manner, forexample, via injection of the compound directly into a solid tumor,often in a depot or sustained release formulation. Furthermore, one mayadminister the drug in a targeted drug delivery system, for example, ina liposome coated with tumor-specific antibody. In this way, theliposomes may be targeted to and taken up selectively by the tumor.

Pharmaceutical compositions of the present invention may be manufacturedby processes well known in the art, e.g., by means of conventionalmixing, dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or lyophilizing processes.

Pharmaceutical compositions for use in accordance with the presentinvention may be formulated in any conventional manner using one or morephysiologically acceptable carriers comprising excipients andauxiliaries which facilitate processing of the active compounds intopreparations which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen.

For injection, the compounds of the invention may be formulated inaqueous solutions, preferably in physiologically compatible buffers suchas Hanks' solution, Ringer's solution, or physiological saline buffer.For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants aregenerally known in the art.

For oral administration, the compounds can be formulated by combiningthe active compounds with pharmaceutically acceptable carriers wellknown in the art. Such carriers enable the compounds of the invention tobe formulated as tablets, pills, lozenges, dragees, capsules, liquids,gels, syrups, slurries, suspensions and the like, for oral ingestion bya patient. Pharmaceutical preparations for oral use can be made using asolid excipient, optionally grinding the resulting mixture, andprocessing the mixture of granules, after adding other suitableauxiliaries if desired, to obtain tablets or dragee cores. Usefulexcipients are, in particular, fillers such as sugars, includinglactose, sucrose, mannitol, or sorbitol, cellulose preparations such as,for example, maize starch, wheat starch, rice starch and potato starchand other materials such as gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/orpolyvinyl-pyrrolidone (PVP). If desired, disintegrating agents may beadded, such as cross-linked polyvinyl pyrrolidone, agar, or alginicacid. A salt such as sodium alginate may also be used.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical compositions which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, a binder such as starch, and/or a lubricant such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. Stabilizers may be added in these formulations, also.Pharmaceutical compositions which may also be used include hard gelatincapsules. The capsules or pills may be packaged into brown glass orplastic bottles to protect the active compound from light. Thecontainers containing the active compound capsule formulation arepreferably stored at controlled room temperature (15-30° C.).

For administration by inhalation, the compounds for use according to thepresent invention may be conveniently delivered in the form of anaerosol spray using a pressurized pack or a nebulizer and a suitablepropellant, e.g., without limitation, dichlorodifluoromethane,trichlorofluoromethane, dichlorotetra-fluoroethane or carbon dioxide. Inthe case of a pressurized aerosol, the dosage unit may be controlled byproviding a valve to deliver a metered amount. Capsules and cartridgesof, for example, gelatin for use in an inhaler or insufflator may beformulated containing a powder mix of the compound and a suitable powderbase such as lactose or starch.

The compounds may also be formulated for parenteral administration,e.g., by bolus injection or continuous infusion. Formulations forinjection may be presented in unit dosage form, e.g., in ampoules or inmulti-dose containers, with an added preservative. The compositions maytake such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulating materials such assuspending, stabilizing and/or dispersing agents.

Pharmaceutical compositions for parenteral administration includeaqueous solutions of a water soluble form, such as, without limitation,a salt, of the active compound. Additionally, suspensions of the activecompounds may be prepared in a lipophilic vehicle. Suitable lipophilicvehicles include fatty oils such as sesame oil, synthetic fatty acidesters such as ethyl oleate and triglycerides, or materials such asliposomes. Aqueous injection suspensions may contain substances whichincrease the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may alsocontain suitable stabilizers and/or agents that increase the solubilityof the compounds to allow for the preparation of highly concentratedsolutions.

Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile, pyrogen-free water,before use.

The compounds may also be formulated in rectal compositions such assuppositories or retention enemas, using, e.g., conventional suppositorybases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the compounds mayalso be formulated as depot preparations. Such long acting formulationsmay be administered by implantation (for example, subcutaneously orintramuscularly) or by intramuscular injection. A compound of thisinvention may be formulated for this route of administration withsuitable polymeric or hydrophobic materials (for instance, in anemulsion with a pharmacologically acceptable oil), with ion exchangeresins, or as a sparingly soluble derivative such as, withoutlimitation, a sparingly soluble salt.

A non-limiting example of a pharmaceutical carrier for the hydrophobiccompounds of the invention is a cosolvent system comprising benzylalcohol, a nonpolar surfactant, a water-miscible organic polymer and anaqueous phase such as the VPD cosolvent system. VPD is a solution of 3%w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80,and 65% w/v polyethylene glycol 300, made up to volume in absoluteethanol. The VPD cosolvent system (VPD: D5W) consists of VPD diluted 1:1with a 5% dextrose in water solution. This cosolvent system dissolveshydrophobic compounds well, and itself produces low toxicity uponsystemic administration. Naturally, the proportions of such a cosolventsystem may be varied considerably without destroying its solubility andtoxicity characteristics. Furthermore, the identity of the cosolventcomponents may be varied: for example, other low-toxicity nonpolarsurfactants may be used instead of polysorbate 80, the fraction size ofpolyethylene glycol may be varied, other biocompatible polymers mayreplace polyethylene glycol, e.g., polyvinyl pyrrolidone, and othersugars or polysaccharides may substitute for dextrose.

Alternatively, other delivery systems for hydrophobic pharmaceuticalcompounds may be employed. Liposomes and emulsions are well knownexamples of delivery vehicles or carriers for hydrophobic drugs. Inaddition, certain organic solvents such as dimethylsulfoxide also may beemployed, although often at the cost of greater toxicity.

Additionally, the compounds may be delivered using a sustained-releasesystem, such as semipermeable matrices of solid hydrophobic polymerscontaining the therapeutic agent. Various sustained-release materialshave been established and are well known by those skilled in the art.Sustained-release capsules may, depending on their chemical nature,release the compounds for a few weeks up to over 100 days. Depending onthe chemical nature and the biological stability of the therapeuticreagent, additional strategies for protein stabilization may beemployed.

The pharmaceutical compositions herein also may comprise suitable solidor gel phase carriers or excipients. Examples of such carriers orexcipients include, but are not limited to, calcium carbonate, calciumphosphate, various sugars, starches, cellulose derivatives, gelatin, andpolymers such as polyethylene glycols.

Many of the SIK2-modulating compounds of the invention may be providedas physiologically acceptable salts wherein the claimed compound mayform the negatively or the positively charged species. Examples of saltsin which the compound forms the positively charged moiety include,without limitation, quaternary ammonium (defined elsewhere herein),salts such as the hydrochloride, sulfate, carbonate, lactate, tartrate,malate, maleate, succinate wherein the nitrogen atom of the quaternaryammonium group is a nitrogen of the selected compound of this inventionwhich has reacted with the appropriate acid. Salts in which a compoundof this invention forms the negatively charged species include, withoutlimitation, the sodium, potassium, calcium and magnesium salts formed bythe reaction of a carboxylic acid group in the compound with anappropriate base (e.g. sodium hydroxide (NaOH), potassium hydroxide(KOH), calcium hydroxide (Ca(OH)₂), etc.).

Pharmaceutical compositions suitable for use in the present inventioninclude compositions wherein the active ingredients are contained in anamount sufficient to achieve the intended purpose, e.g., the modulationof protein kinase activity and/or the treatment or prevention of aprotein kinase-related disorder.

More specifically, a therapeutically effective amount means an amount ofcompound effective to prevent, alleviate or ameliorate symptoms ofdisease or prolong the survival of the subject being treated.

Determination of a therapeutically effective amount is well within thecapability of those skilled in the art, especially in light of thedetailed disclosure provided herein.

For any compound used in the methods of the invention, thetherapeutically effective amount or dose can be estimated initially fromcell culture assays. Then, the dosage can be formulated for use inanimal models so as to achieve a circulating concentration range thatincludes the IC₅₀ as determined in cell culture (i.e., the concentrationof the test compound which achieves a half-maximal inhibition of theSIK2 (SEQ ID NO: 11), or surrogate marker activity). Such informationcan then be used to more accurately determine useful doses in humans.

Toxicity and therapeutic efficacy of the compounds described herein canbe determined by standard pharmaceutical procedures in cell cultures orexperimental animals, e.g., by determining the IC₅₀ and the LD₅₀ (bothof which are discussed elsewhere herein) for a subject compound. Thedata obtained from these cell culture assays and animal studies can beused in formulating a range of dosage for use in humans. The dosage mayvary depending upon the dosage form employed and the route ofadministration utilized. The exact formulation, route of administrationand dosage can be chosen by the individual physician in view of thepatient's condition. (See, e.g., GOODMAN & GILMAN'S THE PHARMACOLOGICALBASIS OF THERAPEUTICS, Ch. 3, 9^(th) ed., Ed. by Hardman, J., andLimbard, L., McGraw-Hill, New York City, 1996, p. 46.)

Dosage amount and interval may be adjusted individually to provideplasma levels of the active species which are sufficient to maintain thekinase modulating effects. These plasma levels are referred to asminimal effective concentrations (MECs). The MEC will vary for eachcompound but can be estimated from in vitro data, e.g., theconcentration necessary to achieve 50-90% inhibition of SIK2 (SEQ ID NO:11), or surrogate marker may be ascertained using the assays describedherein. Dosages necessary to achieve the MEC will depend on individualcharacteristics and route of administration. HPLC assays or bioassayscan be used to determine plasma concentrations.

Dosage intervals can also be determined using MEC value. Compoundsshould be administered using a regimen that maintains plasma levelsabove the MEC for 10-90% of the time, preferably between 30-90% and mostpreferably between 50-90%.

At present, the therapeutically effective amounts of compounds of thepresent invention may range from approximately 2.5 mg/m² to 1500 mg/m²per day. Additional illustrative amounts range from 0.2-1000 mg/qid,2-500 mg/qid, and 20-250 mg/qid.

In cases of local administration or selective uptake, the effectivelocal concentration of the drug may not be related to plasmaconcentration, and other procedures known in the art may be employed todetermine the correct dosage amount and interval.

The amount of a composition administered will, of course, be dependenton the subject being treated, the severity of the affliction, the mannerof administration, the judgment of the prescribing physician, etc.

The compositions may, if desired, be presented in a pack or dispenserdevice, such as an FDA approved kit, which may contain one or more unitdosage forms containing the active ingredient. The pack may for examplecomprise metal or plastic foil, such as a blister pack. The pack ordispenser device may be accompanied by instructions for administration.The pack or dispenser may also be accompanied by a notice associatedwith the container in a form prescribed by a governmental agencyregulating the manufacture, use or sale of pharmaceuticals, which noticeis reflective of approval by the agency of the form of the compositionsor of human or veterinary administration. Such notice, for example, maybe of the labeling approved by the U.S. Food and Drug Administration forprescription drugs or of an approved product insert. Compositionscomprising a compound of the invention formulated in a compatiblepharmaceutical carrier may also be prepared, placed in an appropriatecontainer, and labeled for treatment of an indicated condition. Suitableconditions indicated on the label may include treatment of a tumor,inhibition of angiogenesis, treatment of fibrosis, diabetes, and thelike.

As mentioned above, the compounds and compositions of the invention willfind utility in a broad range of diseases and conditions mediated byprotein kinases, including diseases and conditions mediated by SIK2 (SEQID NO: 3) activity. Such diseases may include by way of example and notlimitation, cancers such as lung cancer, NSCLC (non small cell lungcancer), oat-cell cancer, bone cancer, pancreatic cancer, skin cancer,dermatofibrosarcoma protuberans, cancer of the head and neck, cutaneousor intraocular melanoma, uterine cancer, ovarian cancer, colo-rectalcancer, cancer of the anal region, stomach cancer, colon cancer, breastcancer, gynecologic tumors (e.g., uterine sarcomas, carcinoma of thefallopian tubes, carcinoma of the endometrium, carcinoma of the cervix,carcinoma of the vagina or carcinoma of the vulva), Hodgkin's Disease,hepatocellular cancer, cancer of the esophagus, cancer of the smallintestine, cancer of the endocrine system (e.g., cancer of the thyroid,pancreas, parathyroid or adrenal glands), sarcomas of soft tissues,cancer of the urethra, cancer of the penis, prostate cancer(particularly hormone-refractory), chronic or acute leukemia, solidtumors of childhood, hypereosinophilia, lymphocytic lymphomas, cancer ofthe bladder, cancer of the kidney or ureter (e.g., renal cell carcinoma,carcinoma of the renal pelvis), pediatric malignancy, neoplasms of thecentral nervous system (e.g., primary CNS lymphoma, spinal axis tumors,medulloblastoma, brain stem gliomas or pituitary adenomas), Barrett'sesophagus (pre-malignant syndrome), neoplastic cutaneous disease,psoriasis, mycoses fungoides, and benign prostatic hypertrophy, diabetesrelated diseases such as diabetic retinopathy, retinal ischemia, andretinal neovascularization, hepatic cirrhosis, angiogenesis,cardiovascular disease such as atherosclerosis, immunological diseasesuch as autoimmune disease and renal disease.

The inventive compound can be used in combination with one or more otherchemotherapeutic agents. The dosage of the inventive compounds may beadjusted for any drug-drug reaction. In one embodiment, thechemotherapeutic agent is selected from the group consisting of mitoticinhibitors, alkylating agents, anti-metabolites, cell cycle inhibitors,enzymes, topoisomerase inhibitors such as CAMPTOSAR (irinotecan),biological response modifiers, anti-hormones, antiangiogenic agents suchas MMP-2, MMP-9 and COX-2 inhibitors, anti-androgens, platinumcoordination complexes (cisplatin, etc.), substituted ureas such ashydroxyurea; methylhydrazine derivatives, e.g., procarbazine;adrenocortical suppressants, e.g., mitotane, aminoglutethimide, hormoneand hormone antagonists such as the adrenocorticosteriods (e.g.,prednisone), progestins (e.g., hydroxyprogesterone caproate), estrogens(e.g., diethylstilbesterol), antiestrogens such as tamoxifen, androgens,e.g., testosterone propionate, and aromatase inhibitors, such asanastrozole, and AROMASIN (exemestane).

Examples of alkylating agents that the above method can be carried outin combination with include, without limitation, fluorouracil (5-FU)alone or in further combination with leukovorin; other pyrimidineanalogs such as UFT, capecitabine, gemcitabine and cytarabine, the alkylsulfonates, e.g., busulfan (used in the treatment of chronicgranulocytic leukemia), improsulfan and piposulfan; aziridines, e.g.,benzodepa, carboquone, meturedepa and uredepa; ethyleneimines andmethylmelamines, e.g., altretamine, triethylenemelamine,triethylenephosphoramide, triethylenethiophosphoramide andtrimethylolmelamine; and the nitrogen mustards, e.g., chlorambucil (usedin the treatment of chronic lymphocytic leukemia, primarymacroglobulinemia and non-Hodgkin's lymphoma), cyclophosphamide (used inthe treatment of Hodgkin's disease, multiple myeloma, neuroblastoma,breast cancer, ovarian cancer, lung cancer, Wilm's tumor andrhabdomyosarcoma), estramustine, ifosfamide, novembrichin, prednimustineand uracil mustard (used in the treatment of primary thrombocytosis,non-Hodgkin's lymphoma, Hodgkin's disease and ovarian cancer); andtriazines, e.g., dacarbazine (used in the treatment of soft tissuesarcoma).

Examples of antimetabolite chemotherapeutic agents that the above methodcan be carried out in combination with include, without limitation,folic acid analogs, e.g., methotrexate (used in the treatment of acutelymphocytic leukemia, choriocarcinoma, mycosis fungiodes, breast cancer,head and neck cancer and osteogenic sarcoma) and pteropterin; and thepurine analogs such as mercaptopurine and thioguanine which find use inthe treatment of acute granulocytic, acute lymphocytic and chronicgranulocytic leukemias.

Examples of natural product-based chemotherapeutic agents that the abovemethod can be carried out in combination with include, withoutlimitation, the vinca alkaloids, e.g., vinblastine (used in thetreatment of breast and testicular cancer), vincristine and vindesine;the epipodophyllotoxins, e.g., etoposide and teniposide, both of whichare useful in the treatment of testicular cancer and Kaposi's sarcoma;the antibiotic chemotherapeutic agents, e.g., daunorubicin, doxorubicin,epirubicin, mitomycin (used to treat stomach, cervix, colon, breast,bladder and pancreatic cancer), dactinomycin, temozolomide, plicamycin,bleomycin (used in the treatment of skin, esophagus and genitourinarytract cancer); and the enzymatic chemotherapeutic agents such asL-asparaginase.

An inventive compound can also be used with other signal transductioninhibitors, such as agents that can inhibit EGFR (epidermal growthfactor receptor) responses, such as EGFR antibodies, EGF antibodies, andmolecules that are EGFR inhibitors; VEGF (vascular endothelial growthfactor) inhibitors; and erbB2 receptor inhibitors, such as organicmolecules or antibodies that bind to the erbB2 receptor, such asHERCEPTIN (Genentech, Inc., South San Francisco, Calif.). EGFRinhibitors are described in, for example in WO 95/19970, WO 98/14451, WO98/02434, and U.S. Pat. No. 5,747,498 and such substances can be used inthe present invention as described herein.

EGFR-inhibiting agents include, but are not limited to, the monoclonalantibodies C225 and anti-EGFR 22Mab (ImClone Systems, Inc., New York,N.Y.), the compounds erlotinib (OSI Pharmaceuticals, Inc., Melville,N.Y.), ZD-1839 (AstraZeneca), BIBX-1382 (Boehringer Ingelheim), MDX-447(Medarex Inc., Annandale, N.J.), and OLX-103 (Merck & Co., WhitehouseStation, N.J.), and EGF fusion toxin (Seragen Inc., Hopkinton, Mass.).

These and other EGFR-inhibiting agents can be used in the presentinvention. VEGF inhibitors, for example SU-5416 and SU-6668 (Sugen Inc.,South San Francisco, Calif.), can also be combined with an inventivecompound. VEGF inhibitors are described in, for example, WO 01/60814 A3,WO 99/24440, PCT International Application PCT/IB99/00797, WO 95/21613,WO 99/61422, U.S. Pat. No. 5,834,504, WO 01/60814, WO 98/50356, U.S.Pat. No. 5,883,113, U.S. Pat. No. 5,886,020, U.S. Pat. No. 5,792,783, WO99/10349, WO 97/32856, WO 97/22596, WO 98/54093, WO 98/02438, WO99/16755, and WO 98/02437, all of which are incorporated herein in theirentireties by reference. Other examples of some specific VEGF inhibitorsuseful in the present invention are IM862 (Cytran Inc., Kirkland,Wash.); anti-VEGF monoclonal antibody of Genentech, Inc.; and angiozyme,a synthetic ribozyme from Ribozyme (Boulder, Colo.) and Chiron(Emeryville, Calif.). These and other VEGF inhibitors can be used in thepresent invention as described herein. Further, pErbB2 receptorinhibitors, such as GW-282974 (Glaxo Wellcome plc), and the monoclonalantibodies AR-209 (Aronex Pharmaceuticals Inc., The Woodlands, Tex.) and2B-1 (Chiron), can furthermore be combined with an inventive compound,for example, those indicated in WO 98/02434, WO 99/35146, WO 99/35132,WO 98/02437, WO 97/13760, WO 95/19970, U.S. Pat. No. 5,587,458 and U.S.Pat. No. 5,877,305, which are all hereby incorporated herein in theirentireties by reference. ErbB2 receptor inhibitors useful in the presentinvention are also described in U.S. Pat. No. 6,284,764, incorporated inits entirety herein by reference. The erbB2 receptor inhibitor compoundsand substance described in the aforementioned PCT applications, U.S.patents, and U.S. provisional applications, as well as other compoundsand substances that inhibit the erbB2 receptor, can be used with aninventive compound, in accordance with the present invention.

An inventive compound can also be used with other agents useful intreating cancer, including, but not limited to, agents capable ofenhancing antitumor immune responses, such as CTLA4 (cytotoxiclymphocyte antigen 4) antibodies, and other agents capable of blockingCTLA4; and anti-proliferative agents such as other farnesyl proteintransferase inhibitors, for example the farnesyl protein transferaseinhibitors described in the references cited in the “Background”section, of U.S. Pat. No. 6,258,824 B1.

The above method can also be carried out in combination with radiationtherapy, wherein the amount of an inventive compound in combination withthe radiation therapy is effective in treating the above diseases.Techniques for administering radiation therapy are known in the art, andthese techniques can be used in the combination therapy describedherein. The administration of the compound of the invention in thiscombination therapy can be determined as described herein.

The invention will be further understood upon consideration of thefollowing non-limiting Examples. In other aspects or embodiments areincluded any of the compounds in Table 1, Tables 2, 2A, 2B, and Table 3that fall with in the scope of any of the embodiments described above ofthe compounds of Formula I, IA and IB, or pharmaceuticals acceptablesalts thereof

TABLE 1 List of Examples EX. Structure Chemical Name Mol. Wt 1

3-(2-methoxyphenyl)-4-(thiophen-3-yl)-1H- pyrrolo[2,3-b]pyridine 307.2 2

3-(2,4-difluorophenyl)-4-(thiophen-3-yl)-1H- pyrazolo[3,4-b]pyridine312.8 3

3-(4-chloro-2-fluorophenyl)-4-(thiophen-3-yl)-1H-pyrazolo[3,4-b]pyridine 329.78 4

3-(4-fluoro-2-methoxyphenyl)-4-(thiophen-3-yl)-1H-pyrazolo[3,4-b]pyridine 325.36 5

3-(2-ethoxyphenyl)-4-(thiophen-3-yl)-1H- pyrazolo[3,4-b]pyridine 321.406

3-(4-chloro-2-methoxyphenyl)-4-(thiophen-3-yl)-1H-pyrazolo[3,4-b]pyridine 341.81 7

3-(4-methoxyphenyl)-4-(thiophen-3-yl)-1H- pyrazolo[3,4-b]pyridine 307.378

4-(thiophen-3-yl)-3-(2- (trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridine 345.34 9

3-(2-fluorophenyl)-4-(thiophen-3-yl)-1H- pyrazolo[3,4-b]pyridine 295.3310

3-(2-chloro-3-fluorophenyl)-4-(thiophen-3-yl)-1H-pyrazolo[3,4-b]pyridine 329.78 11

3-(4-(4-methylpiperazin-1-yl)phenyl)-4-(thiophen-3-yl)-1H-pyrazolo[3,4-b]pyridine 375.49 12

2,2,2-trifluoro-1-(4-(4-(4-(thiophen-3-yl)- 1H-pyrazolo[3,4-b]pyridin-3-yl)phenyl)piperazin-1-yl)ethanone 457.47 13

4-(3-(2-chloro-3-fluorophenyl)-1H- pyrazolo[3,4-b]pyridin-4-yl)-2-methylthiazole 344.79 14

4-(3-(4-chloro-2-methoxyphenyl)-1H- pyrazolo[3,4-b]pyridin-4-yl)-2-methylthiazole 356.83 15

4-(thiophen-3-yl)-1H-pyrazolo[3,4- b]pyridine 201.25 16

3-fluoro-4-(thiophen-3-yl)-1H-pyrazolo[3,4- b]pyridine 219.24 17

3-(2-methoxyphenyl)-4-(thiophen-3-yl)-1H- pyrrolo[2,3-b]pyridine 306.38218

3-(2,4-difluorophenyl)-4-(thiophen-3-yl)-1H- pyrrolo[2,3-b]pyridine312.337 19

4-(2-methoxyphenyl)-1H-pyrrolo[2,3- b]pyridine 224.258 20

4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine 200.260 21

4-(thiophen-3-yl)-3-(2- (trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine 344.354 22

3-(2-fluorophenyl)-4-(thiophen-3-yl)-1H- pyrrolo[2,3-b]pyridine 294.34623

3-(2-chloro-3-fluorophenyl)-4-(thiophen-3- yl)-1H-pyrrolo[2,3-b]pyridine328.791 24

3-(4-chloro-2-methoxyphenyl)-4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine 340.827 25

3-(4-methoxyphenyl)-4-(thiophen-3-yl)-1H- pyrrolo[2,3-b]pyridine 306.38226

3-(2-ethoxyphenyl)-4-(thiophen-3-yl)-1H- pyrrolo[2,3-b]pyridine 320.40827

3-(4-chloro-2-fluorophenyl)-4-(thiophen-3- yl)-1H-pyrrolo[2,3-b]pyridine328.791 28

3-(4-fluoro-2-methoxyphenyl)-4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine 324.372 29

4-chloro-3-(thiophen-3-yl)-1H-pyrrolo[2,3- b]pyridine 234.705 30

4-(2-methoxyphenyl)-3-(thiophen-3-yl)-1H- pyrrolo[2,3-b]pyridine 306.38231

3-(2-methoxyphenyl)-4-(5-methylthiophen- 2-yl)-1H-pyrrolo[2,3-b]pyridine320.408 32

3-(2,4-difluorophenyl)-4-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridine 326.363 33

3-(4-chloro-2-methoxyphenyl)-4-(5- methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridine 354.853 34

4-(5-methylthiophen-2-yl)-3-(2- (trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine 358.380 35

3-(2-fluorophenyl)-4-(5-methylthiophen-2- yl)-1H-pyrrolo[2,3-b]pyridine308.373 36

3-(2-methoxypyridin-3-yl)-4-(thiophen-3-yl)- 1H-pyrrolo[2,3-b]pyridine307.370 37

4-(3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2-yl)morpholine 362.448 38

3-(2-chloro-3-fluorophenyl)-4-(5- methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridine 342.818 39

3-(4-chloro-2-fluorophenyl)-4-(5- methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridine 342.818 40

3-(4-fluoro-2-methoxyphenyl)-4-(5- methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridine 338.399 41

3-(4-methoxyphenyl)-4-(5-methylthiophen- 2-yl)-1H-pyrrolo[2,3-b]pyridine320.408 42

3-(2-ethoxyphenyl)-4-(5-methylthiophen-2- yl)-1H-pyrrolo[2,3-b]pyridine334.435 43

3-(2-methoxypyridin-3-yl)-4-(3- methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridine 321.396 44

4-(3-(4-(3-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2- yl)morpholine 376.475 45

4-(5-chlorothiophen-2-yl)-3-(2- methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine340.827 46

4-(5-chlorothiophen-2-yl)-3-(4- methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine340.827 47

3-(3-chlorophenyl)-4-(thiophen-3-yl)-1H- pyrrolo[2,3-b]pyridine 310.80148

3-(3-chlorophenyl)-4-(5-methylthiophen-3- yl)-1H-pyrrolo[2,3-b]pyridine324.827 49

3-(3-chlorophenyl)-4-(5-chlorothiophen-3- yl)-1H-pyrrolo[2,3-b]pyridine345.246 50

4-(5-chlorothiophen-3-yl)-3-(2,4-difluorophenyl)-1H-pyrrolo[2,3-b]pyridine 346.782 51

3-(4-chloro-2-methoxyphenyl)-4-(5- chlorothiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine 375.272 52

4-(5-chlorothiophen-3-yl)-3-(2- (trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine 378.799 53

4-(5-chlorothiophen-3-yl)-3-(2- fluorophenyl)-1H-pyrrolo[2,3-b]pyridine328.791 54

3-(2-chloro-3-fluorophenyl)-4-(5- chlorothiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine 363.236 55

3-(4-chloro-2-fluorophenyl)-4-(5- chlorothiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine 363.236 56

4-(5-chlorothiophen-3-yl)-3-(4-fluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine 358.817 57

4-(5-chlorothiophen-3-yl)-3-(2- ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine354.853 58

3-(2-methoxyphenyl)-4-(5-methylthiophen-2-yl)-1H-pyrazolo[3,4-b]pyridine 321.396 59

3-(2,4-difluorophenyl)-4-(5-methylthiophen-2-yl)-1H-pyrazolo[3,4-b]pyridine 327.351 60

3-(4-chloro-2-fluorophenyl)-4-(5- methylthiophen-2-yl)-1H-pyrazolo[3,4-b]pyridine 343.806 61

3-(4-fluoro-2-methoxyphenyl)-4-(5- methylthiophen-2-yl)-1H-pyrazolo[3,4-b]pyridine 339.387 62

3-(2-ethoxyphenyl)-4-(5-methylthiophen-2- yl)-1H-pyrazolo[3,4-b]pyridine335.423 63

3-(4-chloro-2-methoxyphenyl)-4-(5- methylthiophen-2-yl)-1H-pyrazolo[3,4-b]pyridine 355.841 64

3-(4-methoxyphenyl)-4-(5-methylthiophen-2-yl)-1H-pyrazolo[3,4-b]pyridine 321.396 65

4-(5-methylthiophen-2-yl)-3-(2-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4- b]pyridine 359.368 66

3-(2-fluorophenyl)-4-(5-methylthiophen-2- yl)-1H-pyrazolo[3,4-b]pyridine309.361 67

3-(2-chloro-3-fluorophenyl)-4-(5- methylthiophen-2-yl)-1H-pyrazolo[3,4-b]pyridine 343.806 68

3-(3-chlorophenyl)-4-(5-methylthiophen-2- yl)-1H-pyrazolo[3,4-b]pyridine325.815 69

3-(2-methoxypyridin-3-yl)-4-(5- methylthiophen-2-yl)-1H-pyrazolo[3,4-b]pyridine 322.384 70

4-(3-(4-(5-methylthiophen-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyridin-2- yl)morpholine 377.463 71

4-(5-chlorothiophen-2-yl)-3-(2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridine 341.815 72

4-(5-chlorothiophen-2-yl)-3-(2,4-difluorophenyl)-1H-pyrazolo[3,4-b]pyridine 347.770 73

3-(4-chloro-2-fluorophenyl)-4-(5- chlorothiophen-2-yl)-1H-pyrazolo[3,4-b]pyridine 364.224 74

4-(5-chlorothiophen-2-yl)-3-(4-fluoro-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridine 359.805 75

4-(5-chlorothiophen-2-yl)-3-(2- ethoxyphenyl)-1H-pyrazolo[3,4-b]pyridine355.841 76

3-(4-chloro-2-methoxyphenyl)-4-(5- chlorothiophen-2-yl)-1H-pyrazolo[3,4-b]pyridine 376.260 77

4-(5-chlorothiophen-2-yl)-3-(4-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridine 341.815 78

4-(5-chlorothiophen-2-yl)-3-(2-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4- b]pyridine 379.787 79

4-(5-chlorothiophen-2-yl)-3-(2- fluorophenyl)-1H-pyrazolo[3,4-b]pyridine329.779 80

3-(2-chloro-3-fluorophenyl)-4-(5- chlorothiophen-2-yl)-1H-pyrazolo[3,4-b]pyridine 364.224 81

3-(3-chlorophenyl)-4-(5-chlorothiophen-2- yl)-1H-pyrazolo[3,4-b]pyridine346.234 82

3-(2-methoxypyridin-3-yl)-4-(5- methylthiophen-2-yl)-1H-pyrazolo[3,4-b]pyridine 322.384 83

4-(3-(4-(5-chlorothiophen-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyridin-2- yl)morpholine 397.881 84

3-(2-methoxyphenyl)-4-(4-methylthiophen- 2-yl)-1H-pyrrolo[2,3-b]pyridine320.408 85

4-((5-(3-(2-methoxyphenyl)-1H-pyrrolo[2,3- b]pyridin-4-yl)thiophen-2-yl)methyl)morpholine 405.513 86

3-(2,4-dimethoxyphenyl)-4-(thiophen-3-yl)- 1H-pyrrolo[2,3-b]pyridine336.408 87

3-(2,4-dimethoxyphenyl)-4-(thiophen-3-yl)- 1H-pyrazolo[3,4-b]pyridine337.396 88

N-(4-fluoro-2-methoxyphenyl)-4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-amine 339.387 89

N,N-dimethyl-2-((4-(thiophen-3-yl)-1H- pyrrolo[2,3-b]pyridin-3-yl)amino)benzenesulfonamide 398.502 90

N,N-dimethyl-3-(4-(thiophen-3-yl)-1H- pyrrolo[2,3-b]pyridin-3-yl)benzenesulfonamide 383.487 91

N-(tert-butyl)-N-methyl-3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-3- yl)benzenesulfonamide 425.567 92

N,N-dimethyl-4-(4-(thiophen-3-yl)-1H- pyrrolo[2,3-b]pyridin-3-yl)benzenesulfonamide 383.487 93

N,N-diethyl-3-(4-(thiophen-3-yl)-1H- pyrrolo[2,3-b]pyridin-3-yl)benzenesulfonamide 411.540 94

N,N-dimethyl-2-(4-(thiophen-3-yl)-1H- pyrrolo[2,3-b]pyridin-3-yl)benzenesulfonamide 383.487 95

N,N-diethyl-2-(4-(thiophen-3-yl)-1H- pyrrolo[2,3-b]pyridin-3-yl)benzenesulfonamide 411.540 96

3-(4-(azetidin-1-ylsulfonyl)phenyl)-4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine 395.498 97

3-(3-(pyrrolidin-1-ylsulfonyl)phenyl)-4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine 409.524 98

3-(4-(pyrrolidin-1-ylsulfonyl)phenyl)-4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine 409.524 99

4-(thiophen-3-yl)-3-(2- (trifluoromethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridine 360.353 100

3-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine 378.343 101

3-(2,6-dimethoxypyridin-3-yl)-4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine 337.396 102

3-(2-methoxypyridin-3-yl)-4-(3- methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridine 321.396 103

4-(3,3-difluoroazetidin-1-yl)-3-(2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine 315.317 104

4-(2-methoxyazetidin-1-yl)-3-(2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine 309.362 105

3-(2-methoxyphenyl)-4-(4- (methylsulfonyl)piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine 386.468 106

3-(2-methoxyazetidin-1-yl)-4-(thiophen-3- yl)-1H-pyrrolo[2,3-b]pyridine285.364 107

3-(4-(methylsulfonyl)piperazin-1-yl)-4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine 362.470 108

3-(2-methoxyphenyl)-4-(3-methylthiophen- 2-yl)-1H-pyrrolo[2,3-b]pyridine320.408 109

3-methoxy-N,N-dimethyl-4-((4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-3- yl)amino)benzenesulfonamide 428.528 110

4-methoxy-N,N-dimethyl-3-((4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-3- yl)amino)benzenesulfonamide 428.528 111

N-(4-chloro-3-(morpholinosulfonyl)phenyl)-4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin- 3-amine 474.984 112

N-(2-methoxy-5- (morpholinosulfonyl)phenyl)-4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-amine 470.564 113

3-(2-methoxyphenyl)-5-(thiophen-3-yl)-1H- pyrrolo[2,3-b]pyridine 306.382114

3-(2-chloro-3-fluorophenyl)-5-(thiophen-3- yl)-1H-pyrrolo[2,3-b]pyridine328.791 115

3-(2-methoxyphenyl)-5-(5-methylfuran-2- yl)-1H-pyrrolo[2,3-b]pyridine304.343 116

3-(2-chloro-3-fluorophenyl)-4-(5-methylfuran-2-yl)-1H-pyrrolo[2,3-b]pyridine 326.752 117

2-fluoro-6-(4-(thiophen-3-yl)-1H- pyrrolo[2,3-b]pyridin-3-yl)phenol310.345 118

2-(4-(thiophen-3-yl)-1H-pyrrolo[2,3- b]pyridin-3-yl)phenol 292.355 119

2,4-difluoro-6-(4-(thiophen-3-yl)-1H- pyrrolo[2,3-b]pyridin-3-yl)phenol328.336 120

3-(3-fluoro-2-methoxyphenyl)-4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine 324.372 121

3-(3,5-difluoro-2-methoxyphenyl)-4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine 342.362 122

2-fluoro-6-(5-(thiophen-3-yl)-1H- pyrrolo[2,3-b]pyridin-3-yl)phenol310.345 123

2-(5-(thiophen-3-yl)-1H-pyrrolo[2,3- b]pyridin-3-yl)phenol 292.355 124

2,4-difluoro-6-(5-(thiophen-3-yl)-1H- pyrrolo[2,3-b]pyridin-3-yl)phenol328.336 125

3-(3-fluoro-2-methoxyphenyl)-5-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine 324.372 126

3-(3,5-difluoro-2-methoxyphenyl)-5-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine 342.362 127

2-fluoro-6-(4-(5-methylfuran-2-yl)-1H- pyrrolo[2,3-b]pyridin-3-yl)phenol308.306 128

2-fluoro-6-(5-(5-methylfuran-2-yl)-1H- pyrrolo[2,3-b]pyridin-3-yl)phenol308.306 129

3-(2-chloro-3-fluorophenyl)-5-(5-methylfuran-2-yl)-1H-pyrrolo[2,3-b]pyridine 326.752 130

3-(2-chloro-3-fluorophenyl)-5-(5- methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridine 342.818 131

3-(2-chloro-3-fluorophenyl)-5-(4- methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridine 342.818 132

5-(3-(2-chloro-3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiophene-2- carbonitrile 353.801 133

4-((5-(3-(2-chloro-3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiophen-2- yl)methyl)morpholine 427.922 134

5-chloro-N-(3-(2-chloro-3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-methylthiazol- 2-amine 393.265 135

3-(3-(2-chloro-3-fluorophenyl)-1H- pyrrolo[2,3-b]pyridin-5-yl)-N,N-dimethylbenzenesulfonamide 429.895 136

3-(3,3-difluoroazetidin-1-yl)-5-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine 291.319 137

5-(3-(2-chloro-3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methylthiazole 343.806 138

3-(3-chloro-2-fluorophenyl)-5-(thiophen-3- yl)-1H-pyrrolo[2,3-b]pyridine328.791 139

3-(2-chlorophenyl)-5-(thiophen-3-yl)-1H- pyrrolo[2,3-b]pyridine 310.801140

3-(3-chloro-4-fluorophenyl)-5-(thiophen-3- yl)-1H-pyrrolo[2,3-b]pyridine328.791 141

3-(2-chloro-3-fluoropyridin-4-yl)-5-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine 329.779 142

4-((5-(3-(3-fluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiophen-2- yl)methyl)morpholine 423.503 143

4-((5-(3-(3,5-difluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiophen-2- yl)methyl)morpholine 441.494 144

4-(5-(3-(3-fluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiophen-2- yl)morpholine 409.477 145

4-(5-(3-(3,5-difluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiophen-2- yl)morpholine 427.467 146

3-(3-fluoro-2-methoxyphenyl)-5-(5-(4-methylpiperazin-1-yl)thiophen-2-yl)-1H- pyrrolo[2,3-b]pyridine 422.518147

3-(3,5-difluoro-2-methoxyphenyl)-5-(5-(4-methylpiperazin-1-yl)thiophen-2-yl)-1H- pyrrolo[2,3-b]pyridine 440.509148

5-(5-chlorothiophen-2-yl)-3-(3-fluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine 358.817

TABLE 2 List of further Examples: Mol. EX. Structure Chemical Name Wt149

N-(3-fluoro-4-(4-methylpiperazin-1- yl)phenyl)-4-(thiophen-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine 408.50 150

N-(4-((4-methylpiperazin-1- yl)methyl)phenyl)-4-(thiophen-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine 404.53 151

3-(2-methoxyphenyl)-4-(4-(pyrrolidin-1-ylsulfonyl)phenyl)-1H-pyrazolo[3,4- b]pyridine 434.52 152

N-(2,2-difluorocyclopropyl)-4-(thiophen-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine 292.31 153

4-(4-fluoro-3-(4-(thiophen-3-yl)-1H- pyrazolo[3,4-b]pyridin-3-yl)phenyl)morpholine 380.44 154

4-(6-fluoro-5-(4-(thiophen-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyridin-3- yl)morpholine 381.43 155

3-(2-fluoro-5-(4-methylpiperazin-1- yl)phenyl)-4-(thiophen-3-yl)-1H-pyrazolo[3,4-b]pyridine 393.48 156

3-(2-fluoro-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-4-(thiophen-3-yl)-1H- pyrazolo[3,4-b]pyridine 394.47157

N-(3-morpholinophenyl)-4-(thiophen-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine 377.46 158

N-(3-(4-methylpiperazin-1-yl)phenyl)-4-(thiophen-3-yl)-1H-pyrazolo[3,4-b]pyridin- 3-amine 390.50 159

4-(3-(4-(thiophen-3-yl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-4-(trifluoromethoxy)phenyl)morpholine 446.45 160

3-(5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)-4-(thiophen-3- yl)-1H-pyrazolo[3,4-b]pyridine459.49 161

4-(3-(2-methoxyphenyl)-1H-pyrazolo[3,4- b]pyridin-4-yl)-2-methylthiazole322.38 162

4-(2-methoxy-5-(4-(thiophen-3-yl)-1H- pyrazolo[3,4-b]pyridin-3-yl)phenyl)morpholine 392.47 163

3-(4-methoxy-3-(4-methylpiperazin-1- yl)phenyl)-4-(thiophen-3-yl)-1H-pyrazolo[3,4-b]pyridine 405.52 164

3-(3-chlorophenyl)-4-(thiophen-3-yl)-1H- pyrazolo[3,4-b]pyridine 311.79165

4-(2-methoxy-5-(4-(2-methylthiazol-4-yl)- 1H-pyrazolo[3,4-b]pyridin-3-yl)phenyl)morpholine 407.49 166

4-(3-(4-methoxy-3-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)- 2-methylthiazole 420.53 167

5-(5-chlorothiophen-2-yl)-3-(3,5-difluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine 376.80 168

3-(3-fluoro-2-methoxyphenyl)-5-(5- methylfuran-2-yl)-1H-pyrrolo[2,3-b]pyridine 322.33 169

3-(3,5-difluoro-2-methoxyphenyl)-5-(5- methylfuran-2-yl)-1H-pyrrolo[2,3-b]pyridine 340.32 170

4-(4-fluoro-2-methoxy-3-(5-(thiophen-3- yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)morpholine 409.47 171

3-(6-fluoro-2-methoxy-3-(4- methylpiperazin-1-yl)phenyl)-5-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine 422.51 172

4-(4-fluoro-2-methoxy-3-(5-(5- methylfuran-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)morpholine 407.43 173

3-(6-fluoro-2-methoxy-3-(4- methylpiperazin-1-yl)phenyl)-5-(5-methylfuran-2-yl)-1H-pyrrolo[2,3- b]pyridine 420.47 174

3-(3-fluoro-2-methoxyphenyl)-5-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)-1H- pyrrolo[2,3-b]pyridine 407.50175

3-(3-fluoro-2-methoxyphenyl)-5-(5-(piperidin-1-ylmethyl)thiophen-2-yl)-1H- pyrrolo[2,3-b]pyridine 421.53176

4-(5-(3-(3-fluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazol-2- yl)morpholine 410.46 177

3-(3,5-difluoro-2-methoxyphenyl)-5-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)-1H- pyrrolo[2,3-b]pyridine 425.49178

3-(3,5-difluoro-2-methoxyphenyl)-5-(5-(piperidin-1-ylmethyl)thiophen-2-yl)-1H- pyrrolo[2,3-b]pyridine 439.51179

4-(5-(3-(3,5-difluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazol-2- yl)morpholine 428.45 180

N-(tert-butyl)-3-(3-(3-fluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methylbenzenesulfonamide 467.55 181

N-(tert-butyl)-3-(3-(3,5-difluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methylbenzenesulfonamide 485.54 182

3-(3-fluoro-2-methoxyphenyl)-5-(3- (pyrrolidin-1-ylsulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine 451.51 183

3-(3,5-difluoro-2-methoxyphenyl)-5-(3-(pyrrolidin-1-ylsulfonyl)phenyl)-1H- pyrrolo[2,3-b]pyridine 469.50 184

3-(3-(3-fluoro-2-methoxyphenyl)-1H- pyrrolo[2,3-b]pyridin-5-yl)-N,N-dimethylbenzenesulfonamide 425.76 185

3-(3-(3,5-difluoro-2-methoxyphenyl)-1H- pyrrolo[2,3-b]pyridin-5-yl)-N,N-dimethylbenzenesulfonamide 443.46 186

N-(3-chloro-4-morpholinophenyl)-3-(3-fluoro-2-methoxyphenyl)-1H-pyrrolo[2,3- b]pyridin-5-amine 452.90 187

N-(3-chloro-4-morpholinophenyl)-3-(3,5-difluoro-2-methoxyphenyl)-1H-pyrrolo[2,3- b]pyridin-5-amine 470.89 188

3-(3-fluoro-2-methoxyphenyl)-N-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1H- pyrrolo[2,3-b]pyridin-5-amine449.49 189

3-(3,5-difluoro-2-methoxyphenyl)-N-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-amine 467.48 190

3-(3-fluoro-2-methoxyphenyl)-5-(1- (piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine 391.44 191

3-(3,5-difluoro-2-methoxyphenyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H- pyrrolo[2,3-b]pyridine 409.43 192

2-(5-(5-(morpholinomethyl)thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenol 391.486 193

2-fluoro-6-(5-(5- (morpholinomethyl)thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenol 409.477 194

4-((5-(3-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5- yl)thiophen-2-yl)methyl)morpholine455.457 195

4-(5-(3-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazol-2- yl)morpholine 442.439

TABLE 2A List of further Examples: EX. Structure Chemical Name Mol. Wt196

N-(tert-butyl)-3-(3-(2,2- difluorobenzo[d][1,3]dioxol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N- methylbenzenesulfonamide 499.43 197

3-(2,2-difluorobenzo[d][1,3]dioxol- 4-yl)-5-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)-1H- pyrrolo[2,3-b]pyridine 439.47 198

3-(2,2-difluorobenzo[d][1,3]dioxol- 4-yl)-5-(5-(piperidin-1-ylmethyl)thiophen-2-yl)-1H- pyrrolo[2,3-b]pyridine 453.50 199

4-(4-(3-(2,2- difluorobenzo[d][1,3]dioxol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5- yl)thiazol-2-yl)morpholine 442.43 200

4-((5-(3-(2,2- difluorobenzo[d][1,3]dioxol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5- yl)thiophen-2-yl)methyl)morpholine 455.47201

4-(5-(3-(2,2- difluorobenzo[d][1,3]dioxol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5- yl)thiazol-2-yl)morpholine 442.43 202

N-(tert-butyl)-3-(3-(2,2- difluorobenzo[d][1,3]dioxol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N- methylbenzenesulfonamide 499.53 203

3-(2,2-difluorobenzo[d][1,3]dioxol- 5-yl)-5-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)-1H- pyrrolo[2,3-b]pyridine 439.47 204

3-(2,2-difluorobenzo[d][1,3]dioxol- 5-yl)-5-(5-(piperidin-1-ylmethyl)thiophen-2-yl)-1H- pyrrolo[2,3-b]pyridine 453.50 205

4-(4-(3-(2,2- difluorobenzo[d][1,3]dioxol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5- yl)thiazol-2-yl)morpholine 442.43 206

3-(2,2-difluorobenzo[d][1,3]dioxol- 5-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3- b]pyridine 423.41 207

4-(4-(3-(3-fluoro-2- methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazol-2- yl)morpholine 410.46 208

4-(4-(3-(3,5-difluoro-2- methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazol-2- yl)morpholine 428.45 209

3-(2,2-difluorobenzo[d][1,3]dioxol- 4-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3- b]pyridine 423.41 210

(2,6-difluorophenyl)(5-(1- (piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3- yl)methanone 407.41 211

3-(3,5-difluoro-2-methoxyphenyl)- 5-(1-((4-methylpiperazin-1-yl)sulfonyl)-1H-pyrazol-4-yl)-1H- pyrrolo[2,3-b]pyridine 488.51 212

3-(3,5-difluoro-2-methoxyphenyl)- 5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3- b]pyridine 423.45 213

(2,6-difluorophenyl)(5-(2- morpholinothiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-3- yl)methanone 426.43 214

3-(3,5-difluoro-2-methoxyphenyl)- 5-(1-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H- pyrrolo[2,3-b]pyridine 487.52 215

3-(3,5-difluoro-2-methoxyphenyl)- 5-(1-(1-(ethylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H- pyrrolo[2,3-b]pyridine 501.54 216

3-(3,5-difluoro-2-methoxyphenyl)- 5-(1-(1-(propylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H- pyrrolo[2,3-b]pyridine 515.57 217

3-(3,5-difluoro-2-methoxyphenyl)- 5-(4-(4-(methylsulfonyl)piperazin-1-yl)-1H-pyrazol-1-yl)-1H- pyrrolo[2,3-b]pyridine 488.51 218

2-(4-(1-(3-(3,5-difluoro-2- methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4- yl)piperazin-1-yl)ethanol 454.47 219

3-(2,2-difluorobenzo[d][1,3]dioxol- 5-yl)-5-(1-((4-methylpiperazin-1-yl)sulfonyl)-1H-pyrazol-4-yl)-1H- pyrrolo[2,3-b]pyridine 502.49 220

3-(2,2-difluorobenzo[d][1,3]dioxol- 5-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3- b]pyridine 437.44 221

3-(2,2-difluorobenzo[d][1,3]dioxol- 5-yl)-5-(1-(1-(methylsulfonyl)piperidin-4-yl)-1H- pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine 501.50 222

3-(2,2-difluorobenzo[d][1,3]dioxol- 5-yl)-5-(1-(1-(ethylsulfonyl)piperidin-4-yl)-1H- pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine 515.53 223

3-(2,2-difluorobenzo[d][1,3]dioxol- 5-yl)-5-(1-(1-(propylsulfonyl)piperidin-4-yl)-1H- pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine 529.55 224

3-(2,2-difluorobenzo[d][1,3]dioxol- 5-yl)-5-(4-(4-(methylsulfonyl)piperazin-1-yl)-1H- pyrazol-1-yl)-1H-pyrrolo[2,3-b]pyridine 502.49 225

2-(4-(1-(3-(2,2- difluorobenzo[d][1,3]dioxol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H- pyrazol-4-yl)piperazin-1-yl)ethanol468.45 226

2-(4-(4-(3-(3,5-difluoro-2- methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-1- yl)piperidin-1-yl)ethanol 453.48 227

2-(4-(4-(3-(2,2- difluorobenzo[d][1,3]dioxol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H- pyrazol-1-yl)piperidin-1-yl)ethanol467.46 228

3-(3-fluoro-2-methoxyphenyl)-5-(5- (1-(piperidin-1-yl)ethyl)thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridine 435.55

TABLE 2B List of further Examples: Mol. EX. Structure Chemical Name Wt229

3-(3,5-difluoro-2-methoxyphenyl)- 5-(5-(1-(pyrrolidin-1-yl)ethyl)thiophen-2-yl)-1H- pyrrolo[2,3-b]pyridine 439.52 230

3-(3,5-difluoro-2-methoxyphenyl)- 5-(5-(1-(piperidin-1-yl)ethyl)thiophen-2-yl)-1H- pyrrolo[2,3-b]pyridine 453.55 231

3-(3,5-difluoro-2-methoxyphenyl)- 5-(5-(1-(4-methylpiperidin-1-yl)ethyl)thiophen-2-yl)-1H- pyrrolo[2,3-b]pyridine 467.57 232

3-(3,5-difluoro-2-methoxyphenyl)- 5-(5-(1-(4-methylpiperazin-1-yl)ethyl)thiophen-2-yl)-1H- pyrrolo[2,3-b]pyridine 468.56 233

4-(1-(5-(3-(3,5-difluoro-2- methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiophen-2- yl)ethyl)morpholine 455.52 234

3-(2,2-difluorobenzo[d][1,3]dioxol- 5-yl)-5-(5-(1-(pyrrolidin-1-yl)ethyl)thiophen-2-yl)-1H- pyrrolo[2,3-b]pyridine 453.50 235

3-(2,2-difluorobenzo[d][1,3]dioxol- 5-yl)-5-(5-(1-(piperidin-1-yl)ethyl)thiophen-2-yl)-1H- pyrrolo[2,3-b]pyridine 467.53 236

3-(2,2-difluorobenzo[d][1,3]dioxol- 5-yl)-5-(5-(1-(4-methylpiperidin-1-yl)ethyl)thiophen-2-yl)-1H- pyrrolo[2,3-b]pyridine 481.56 237

3-(2,2-difluorobenzo[d][1,3]dioxol- 5-yl)-5-(5-(1-(4-methylpiperazin-1-yl)ethyl)thiophen-2-yl)-1H- pyrrolo[2,3-b]pyridine 482.55 238

4-(1-(5-(3-(2,2- difluorobenzo[d][1,3]dioxol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5- yl)thiophen-2-yl)ethyl)morpholine 469.50 239

3-(2,2-difluorobenzo[d][1,3]dioxol- 4-yl)-5-(5-(1-(pyrrolidin-1-yl)ethyl)thiophen-2-yl)-1H- pyrrolo[2,3-b]pyridine 453.13 240

3-(2,2-difluorobenzo[d][1,3]dioxol- 4-yl)-5-(5-(1-(piperidin-1-yl)ethyl)thiophen-2-yl)-1H- pyrrolo[2,3-b]pyridine 467.53 241

3-(2,2-difluorobenzo[d][1,3]dioxol- 4-yl)-5-(5-(1-(4-methylpiperidin-1-yl)ethyl)thiophen-2-yl)-1H- pyrrolo[2,3-b]pyridine 481.56 242

3-(2,2-difluorobenzo[d][1,3]dioxol- 4-yl)-5-(5-(1-(4-methylpiperazin-1-yl)ethyl)thiophen-2-yl)-1H- pyrrolo[2,3-b]pyridine 482.55 243

4-(1-(5-(3-(2,2- difluorobenzo[d][1,3]dioxol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5- yl)thiophen-2-yl)ethyl)morpholine 469.50

TABLE 3 List of Compounds purchased from vendor library SIK2 Cmpd IC50No Structure Chemical Name Mol. Wt μM 1

4-(3,4-dimethoxyphenyl)-3-(pyridin- 3-yl)-1H-pyrazolo[3,4-b]pyridine332.356 ** 2

3-(benzo[d][1,3]dioxol-5-yl)-4-(3- (trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridine 383.323 * 3

N-(3-(4-(3,4,5-trimethoxyphenyl)- 1H-pyrazolo[3,4-b]pyridin-3-yl)phenyl)methanesulfonamide 454.499 * 4

N-(2-(dimethylamino)ethyl)-3-(3- (3,4,5-trimethoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-4- yl)benzamide 475.54 * 5

3-(2-methoxyphenyl)-4-(thiophen-3- yl)-1H-pyrazolo[3,4-b]pyridine307.370 *** 6

4-(4-isopropylphenyl)-3-(3,4,5- trimethoxyphenyl)-1H-pyrazolo[3,4-b]pyridine 403.474 ** 7

2-((hydroxy(3-(4-(3- (trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)phenyl)methyl)amino)ethanol 426.391 * 8

4-(3-methoxyphenyl)-3-(3- (trifluoromethyl)phenyl)-1H-pyrazolo[3,4-b]pyridine 369.34 * 9

N,N-dimethyl-3-(3-(3,4,5- trimethoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)aniline 404.462 * 10

4-(furan-3-yl)-3-(2-methoxyphenyl)- 1H-pyrazolo[3,4-b]pyridine 292.304*** 11

3-(3-(3,4,5-trimethoxyphenyl)-1H- pyrazolo[3,4-b]pyridin-4- yl)benzamide404.419 * 12

N-methyl-3-(3-(3- (trifluoromethyl)phenyl)-1H- pyrazolo[3,4-b]pyridin-4-yl)benzamide 396.365 * *Kinase Inhibition Result for Selected Compounds*** <0.1 μM, ** >0.1 μM, * >1 μM ND = Not Determined

List of abbereviation and meaning used through out this applicationAbbreviation Meaning CHCl3 Chloroform - CHCl₃ CDCl3 Chloroformdeuterated solvent - CDCl₃ DCM Dichloromethane - CH₂Cl₂ DME1,2-Dimethoxyethane DMF N,N-Dimethylformamide DMSO DimethylsulfoxideDMSO-d₆ Dimethylsulfoxide deuterated solvent Pd2(pda)3Tris(dibenzylideneacetone)dipalladium(0) Pd(PH3)4Tetrakis(trifluorophosphine)palladium(0) PTSA p-Toluene Sulfonic AcidTHF Tetrahydrofuran ±BINAP rac2.2′-Bis(diphenylphosphino)-9,9-dimethylxanthene Xantphos4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene Pd(dppf)Cl₂•CH₂Cl₂[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium II DCM Et EthylMe Methyl MeOH Methanol EtOH Ethanol EtOAc Ethylacetate AcCN/MeCNAcetonitrile DIPEA Diisopropylethylamine IP Isopropanol Na₂CO₃ SodiumCarbonate K₂CO₃ Potassium Carbonate Cs₂CO₃ Cesium Carbonate TFATrifluoroacetic acid EDC HClN-Ethyl-N′-(3-dimethylaminopropyl)carbodiimide HCl HOBT1-Hydroxybenzotgriazole hydrate HOAc Acetic Acid Et Ethyl TMSTrimethylsilyl NBS N-Bromosuccinamide NCS N-Chlorosuccinamide PGProtecting Group g, gm Gram(s) mg Milligram(s) h, hr Hour min Minute(s)M Molar, molarity mM Millimolar μM Micromolar nM Nanomolar L, l Liter(s)mL, mL Milliliter(s) μL Microliter(s) RM Reaction Mixture or ReactionMass SM Starting Material RT, rt Room Temperature HPLC High-PerformanceLiquid Chromatography LCMS Liquid Chromatography Mass Spectrometry MS orms Mass Spectrometry NMR Nuclear Magnetic Resonance Spectroscopy TLCThin Layer Chromatography UV Ultra-Violet Spectrometry s Singlet d, Dt,dt Doublet, doublet of doublet t, tr Triplet m Multiplet

Methods of Preparation of Compounds

In certain embodiments, the Examples depicted below are compoundsprepared according to general procedures given in the followingsections. Although the synthetic methods and Schemes depict thesyntheses of certain compounds of the present invention, the methods andother methods known to one of ordinary skill in the art can be appliedto all the compounds of the genus, the genus sub-class and species ofeach of these compounds as described herein. All aspects of thisinvention can be understood from the following Schemes. The followingare exemplary and are not intended to limit the scope of the invention.

EXAMPLES Experimental Details and Examples

Melting points were determined in a MP-96 digital Polmon apparatus. ¹HNMR and ¹³C NMR spectra were recorded at rt in CDCl3 or DMSO-d6 at Jeol400-MHz NMR spectrophotometer using solvent peaks for CDCl3: 7.27 andDMSO-d6 2.50 (D) as internal references. The assignment of chemicalshifts is based on standard NMR experiments (1H, 13C). Mass spectra wererecorded on a Shimadzu LCMS LC-210EVspectrometer with an API-ESionization source. Jasco-FTIR-4100 was used to record the IR spectra.TLC analyses were performed on silica F254 and detection by UV light at254 nm, or by spraying with phosphomolybdic-H₂SO₄ dyeing reagent, KMNO₄or iodine. Column chromatography were performed on silica Gel 60 (230mesh). Purifications and separations were performed on a standard silicaflash chromatography system. The purity of the samples has beendetermined by HPLC for the % area peak corresponding to the retention ofcompound and elemental analysis for C, H, N and O was carried out usingPerkin-Elmer 2400 elemental analyser and chloride analysis performedusing calorimetric titration at the Intertek USA Inc., QTI. GeneralSynthesis Schemes 1-3

“PG” represents a protecting group, or protecting groups (PGs), andrefers to a group used to protect a certain functional moiety to preventit from participation in chemical reactions until the PG is removed.Well known to the skilled artisan, these protective groups can beremoved by acid, base, and hydrogenolysis conditions in the presence orabsence of organic solvents. Such PGs employed in the above synthesisschemes 1-3 include, but are not limited to, p-methoxybenzyl (PMB),2,4-dimethoxybenzyl, benzyl (Bn), 4-toluenesulfonyl chloride (tosylchloride or TsC1), 2-(trimethylsilyl) ethoxymethyl chloride (SEM-Cl),trityl chloride (triphenylmethyl chloride), dimethoxytrityl,tetrahydropyranyl (THP), di-tert-butyl dicarbonate (tert-Boc),fluorenylmethyloxycarbonyl chloride (FMOC-Cl), tert-butyldimethylsilylchloride (TBDMS-Cl), and carboxybenzyl (Cbz) groups.

Intermediate 6 Preparation of 4-chloro-1H-pyrazolo[3,4-b]pyridine (6)

2,2-dimethyl-1,3-dioxane-4,6-dione 1 (meldrum's acid) (20 g, 139 mmol),1-(4-methoxybenzyl)-1H-pyrazol-5-amine (2) (28.2 g, 139 mmol, 1 eq)(prepared according to the procedure described by Misra, R. N., et al.Bioorg. Med. Chem. Lett. (2003), 13, 1133-1136) in presence oftriethoxymethane (30.8 g, 208 mmol, 1 eq) was heated to 85° C. for 1 hr,subsequently worked up and treated with diethyl ether, and provided thepure5-(((1-(4-methoxybenzyl)-1H-pyrazol-5-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione(3) as yellow solid (39.3 g). To a stirred solution of DOWTHERM™ (80 mL)was added compound 3 (39.3 g at 200° C. under N₂ in portions over a 30min). After completion of additions, the RM was heated at 240° C. for 1hr. After completion of the reaction from TLC, the mixture was dilutedwith hexanes (300 mL) to separate the DOWTHERM™ from the crude RM. Theresulting crude mixture on treatment with DCM and diethyl ether providedthe off-white solid of1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (4) (24.56 g).Chlorination of compound 4 (24 g, 94 mmol) on treatment with phosphoryltrichloride (43 g, 282 mmol) in dichloroethane (10 mL) at 40° C. for 4hr yielded 19 g of4-chloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine 5.

4-Chloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine (5) 19 g (69.4mmol) in neat TFA (30 mL, 389 mmol) was stirred at 80° C. for 4 hr. Theresulting RM was concentrated and MeOH was added and the obtainedprecipitate was filtered and washed with MeOH. The crude solid wastreated with EtOAc, saturated NaHCO₃ and dried over Na₂SO₄, to yield thedesired product as a half white solid. ¹H NMR (400 MHz, CDCl₃): δ 13.23(br s, 1H), 8.52 (d, J=5.1 Hz, 1H), 8.10 (s, 1H), 7.32 (m, 1H).

Intermediate 7 Preparation of3-bromo-4-chloro-1H-pyrazolo[3,4-b]pyridine (7)

4-chloro-1H-pyrazolo[3,4-b]pyridine (6) 1 g (6.53 mmoles) in acetic acid(10 mL) cooled to 0° C. was added N-bromosuccinimide 2.31 g (13.06 mmoland the resulting RM was stirred for 4 hr at rt. After completion of theSM, the RM was quenched with ice water and extracted with dichlromethane(2×10 mL). The combined organic layer was dried over sodium sulphate,and the solvent evaporated to yield compound 7 (Yield: 0.9 g, 60%). ¹HNMR (400 MHz, CDCl₃): δ 13.19 (br s, 1H), 8.21 (s, 1H), 7.39 (m, 1H).

Intermediate 8 Preparation of3-bromo-4-chloro-1-tosyl-1H-pyrazolo[3,4-b]pyridine (8)

To 3-bromo-4-chloro-1H-pyrazolo[3,4-b]pyridine (7) 1 g (4.345 mmol, 1eq) in DMF (5 mL) cooled to 0° C. was add sodium hydride 0.156 g (6.51mmols, 1.5 eq) slowly under nitrogen atmosphere for 15 min followed bythe addition of p-toluene sulfonyl chloride 0.91 g (4.77 mmol, 1.1 eq).The resulting RM was stirred for 2 hr and after completion of the SMsfrom TLC; the RM was quenched with ice cold water and extracted withchloroform. The combined organic layer was washed with brine solutionand the organic layer was dried over sodium sulphate. The solvents wereremoved to get the crude product, which was passed through through100-200 mesh silica gel eluting the pure compound 8 at 6-7% ethylacetate in hexane (Yield: 1.2 g, 72%).

Intermediate 10 Preparation of4-chloro-3-iodo-1-tosyl-1H-pyrazolo[3,4-b]pyridine (10)

A solution of compound 9 (230 mg, 0.8273 mmol) in DMF (7 mL) was cooledto 0° C. and sodium hydride (49 mg, 1.2409 mmol) was added slowly undernitrogen atmosphere and was stirred for 20 min. The PTSA (p-toluenesulfonic acid) was added slowly to the RM and stirred for 2 hrs at RT.After completion of the reaction, the reaction was quenched with icewater and extracted with ethyl acetate twice. The organic layer wascompletely distilled off to get the crude material which was passed over100-200 mesh silica gel eluting the pure compound at 5-6% ethyl acetatein hexane as eluent to get the title compound as half white coloredsolid 10.

General Scheme 4 Synthesis Examples

General Scheme 5 for the Synthesis of Examples

General Procedures for the Preparation Examples

The key intermediates 3-bromo-4-chloro-1H-pyrazolo[3,4-b]pyridine (7) or4-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridineprotected (9) were preparedfrom N-chloro- or N-bromo-succinamide, 2 eq in presence of acetic acidas solvent at rt for 4 to 6 hr, which afforded ˜50-60 yields. Both thecompounds 7 and 9 protected with p-toluenesulfonyl chloride (p-TsCl) (1eq) on treatment with sodium hydride in DMF at rt for 2 hr and aftercompletion of the SMs from TLC; the RM was quenched with ice cold waterand extracted with chloroform. The combined organic layer was washedwith brine solution and the organic layer was dried over sodium sulphateand the solvents were removed to get the crude product, which was passedthrough through 100-200 mesh silica gel eluting the pure compounds 8 and10 at 10% ethyl acetate in hexane and gave greater than 70% yields.

In subsequent step of the Suzuki-Cross coupling reactions, variouslysubstituted aryl boronic acids and/or aryl boronic esters were reactedwith either compound 8 or 10 with 1 eq. each in presence of one of thesolvents: 1,4-dioxane, THF, DMF, DMSO, toluene, or acetonitrile. Theresulting RM was degassed, purged with argon or N₂ gas a few times andwas charged with NaCO₃, Cs₂CO₃, K₂CO₃, tBuOK, Na-tBuOK, potassiumacetate or NaHCO₃ (1.5 to 2 eq) followed by the addition of palladiumcatalysts (0.01 to 0.05 eq). After the addition of catalysts thecontents of the reaction were purged and degassed again and heated at 80to 100° C. for 8 to 16 or 24 hr. After completion of the reactionmonitored from TLC, the contents were cooled to rt and diluted withCH₂Cl₂, CHCl₃ or EtOAc. The organic layers were passed through a Celitepad then the solvent was completely distilled off to get the crudeproduct, which was subjected to flash to column chromatographypurification to get the variously substituted title compounds 11 and 12.

Preparation of Example 13-(2-methoxyphenyl)-4-(thiophen-3-yl)-1H-pyrazolo[3,4-b]pyridine (24)

Step 1:

A stirred solution of (8) (0.150 g 0.387 mmol) and(2-methoxyphenyl)boronic acid (20) (58 mg 0.387 mmol) in acetonitrile(10 mL) was degassed and purged with nitrogen for 10 min. Then cesiumcarbonate (250 mg, 0.774 mmol) and Pd(dppf)Cl₂ (15 mg, 0.019 mmol) wasadded, then again degassed and purged with nitrogen for 15 min and theRM heated to 85° C. for 4 hr in a sealed tube. After completion of thereaction, the RM was cooled to rt and diluted with chloroform andfiltered through celite bed. The organic layer was completely distilledoff to get the crude product, which was passed through 100-200 meshsilica gel eluting the pure compound at 7-8% ethyl aceate in hexane asan off white colored compound 21.

Step 2:

To a stirred solution of4-chloro-3-(2-methoxyphenyl)-1-tosyl-1H-pyrazolo[3,4-b]pyridine (21)(100 mg, 0.242 mmol) and thiophen-3-ylboronic acid (22) (30 mg, 0.242mmol) in acetonitrile (7 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (158 mg, 0.484 mmol) and Pd(PPh₃)₄ (13.9mg, 0.0121 mmol) and again degassed and purged with nitrogen for 15 min.Then the RM was heated to 85° C. overnight in a sealed tube. Aftercompletion of the SM the RM was cooled to rt and diluted withchloroform. The organic layer was passed through a celite bed. Theorganic layer was completely distilled off the solvent to get the crudeproduct, which was passed through 100-200 mesh silica gel eluting thepure compound at 10-11% ethyl acetate in hexane as off white solid3-(2-methoxyphenyl)-4-(thiophen-3-yl)-1-tosyl-1H-pyrazolo[3,4-b]pyridine(23).

Step 3:

To a stirred solution of (23) (50 mg, 0.108 mmol) in methanol (5 mL) andwater (5 mL) was added potassium carbonate (29 mg, 0.216 mmol). The RMwas heated to 60° C. overnight. After completion of the SM, the solventswere completely distilled off and diluted with water and extracted withchloroform twice. The organic layer was dried over sodium sulphate andcompletely distilled off to get the crude product, which was passedthrough 100-200 mesh silica gel eluting the pre compound at 28-30% ethylacetate in hexane as eluent to get the pale yellow colored solid (24).¹H NMR (CDCl3) δ: 11.05 (1H), 8.57 (d, J=4.75 1H), 7.50 (m, J=5.85 1H),7.48 (m, J=5.73 1H), 7.16 (m, J=4.87 1H), 7.12 (m, J=3.17 1H), 6.98 (m,J=4.87 3H), 6.61 (d, J=8.17 1H), 3.21 (3H) and MS m/z=308.1.

Preparation of Example 43-(4-fluoro-2-methoxyphenyl)-4-(thiophen-3-yl)-1H-pyrazolo[3,4-b]pyridine(28)

Step 1:

To a stirred solution of3-bromo-4-chloro-1-tosyl-1H-pyrazolo[3,4-b]pyridine 8 (150 mg 0.387mmol) and (4-fluoro-2-methoxyphenyl)boronic acid 25 (65 mg, 0.387 mmol)in acetonitrile (5 mL), degassed and purged with nitrogen for 10 min,cesium carbonate (252 mg 0.775 mmol) and Pd(dppf)Cl₂ (15 mg, 0.0193mmol) were added. The resulting RM degassed and purged again withnitrogen for 15 min. The RM was heated to 85° C. for 4 hr in a sealedtube. After completion of the reaction, it was cooled to rt and dilutedwith chloroform and filtered through celite bed. The organic layer wascompletely distilled off to get the crude compound 26. The crudematerial was passed through 100-200 mesh silica gel and eluting the purecompound at 7-8% ethyl aceate in hexane obtained off white colored solid26.

Step 2:

To a stirred solution of compound 26 (100 mg, 0.231 mmol) and compound22 (33 mg, 0.254 mmol) in acetonitrile (5 mL), degassed and purged withnitrogen for 10 min, was added cesium carbonate (150 mg, 0.463 mmol) andPd(PPh₃)₄ (13 mg, 0.0115 mmol) and degassed and purged again withnitrogen for 15 min. Then the RM was heated to 85° C. overnight in asealed tube. After completion of the SM, the RM was cooled to rt anddiluted with chloroform and the organic layer was passed through celitebed. The organic layer was completely distilled off to get the crudeproduct, which was passed through 100-200 mesh silica gel eluting thepure compound 27 at 10-11% ethyl acetate in hexane as off white solid.

Step 3:

To a stirred solution of3-(4-fluoro-2-methoxyphenyl)-4-(thiophen-3-yl)-1-tosyl-1H-pyrazolo[3,4-b]pyridine27 (50 mg 0.102 mmol) in methanol (10 mL) and water (5 mL) was addedpotassium carbonate (0.204 mmol) and the RM was heated to 60° C.overnight. After completion of the SM the the solvents was completelydistilled off, diluted with water and extracted with chloroform twice.The organic layer was dried over sodium sulphate. The crude product waspassed through 100-200 mesh silica gel eluting the pre compound at28-30% ethyl acetate in hexane as eluent to get the pale yellow coloredsolid of compound3-(4-fluoro-2-methoxyphenyl)-4-(thiophen-3-yl)-1H-pyrazolo[3,4-b]pyridine28. ¹H NMR (CDCl3) δ: 8.56 (d, 1H), 7.44 (m, 1H), 7.23 (m, 1H), 7.16 (m,1H), 7.02 (m, 1H), 6.95 (m, 1H), 6.73 (m, 1H), 6.34 (m, 1H) and MSm/z=325.8.

Preparation of Example 53-(2-ethoxyphenyl)-4-(thiophen-3-yl)-1H-pyrazolo[3,4-b]pyridine (32)

Step 1:

To a stirred solution of compound 8 (150 mg, 0.387 mmol) and 29 (65 mg,0.387 mmol) in acetonitrile (5 mL), degassed and purged with nitrogenfor 10 min, was add cesium carbonate (252 mg, 0.775 mmol) andPd(dppf)Cl₂ (15 mg, 0.0193 mmol), again degassed and purged withnitrogen for 15 min and the RM was heated to 85° C. for 4 hr in a sealedtube. After completion of the reaction, the RM was cooled to rt anddiluted with chloroform and filtered through celite bed. The organiclayer was completely distilled off to get the crude product, which waspassed through 100-200 mesh silica gel eluting the pure compound at 7-8%ethyl acetate in hexane as off white colored solid 30.

Step 2:

To a stirred solution of 30 (79 mg, 0.163 mmol) and 22 (23 mg, 0.179mmol) in acetonitrile (5 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (107 mg, 0.497 mmol) and Pd(PPh3)₄ (9mg, 0.00817 mmol) and again degassed and purged with nitrogen for 15min. The RM was heated to 85° C. overnight in a sealed tube. Aftercompletion of the SM, the RM was cooled to rt and diluted withchloroform and the organic layer was passed through celite bed. Theorganic layer was completely distilled off the solvent to get the crudeproduct, which was passed through 100-200 mesh silica gel eluting thepure compound at 10-11% ethyl acetate in hexane as off white solidcompound 31.

Step 3:

To a stirred solution of 31 (50 mg, 0.105 mmol) in methanol (40 mL) andwater (5 mL) was added potassium carbonate (30 mg, 0.210 mmol) and theRM heated to 60° C. overnight. After completion of the SM, the solventswere completely distilled off, diluted with water and extracted withchloroform twice. The organic layer was dried over sodium sulphate. Thecrude was passed through 100-200 mesh silica gel eluting the precompound at 28-30% ethyl acetate in hexane as eluent to get the paleyellow colored solid of compound 32. ¹H NMR (CDCl3) δ: 11.28 (s, 1H),8.57 (d, 1H), 7.52 (m, 1H), 7.32 (m, 1H), 7.17 (d, 1H), 7.00 (m, 2H)6.95 (m, 1H), 6.57 (m, 1H); and MS m/z=321.9

Preparation of Example 6 36

Step 1:

To a stirred solution of compound 8 (150 mg, 0.387 mmol) and 33 (72 mg,0.387 mmol) in acetonitrile (5 mL), degassed and purged with nitrogenfor 10 min, was added Cs₂CO₃ (253 mg, 0.775 mmol) and Pd(dppf)Cl₂ (16mg, 0.0193 mmol). The resulting RM was degassed, purged with nitrogenagain for 15 min and was heated to 85° C. for 4 hr in a sealed tube.After completion of the reaction was cooled to rt and diluted withchloroform and filtered through celite bed. The organic layer wascompletely distilled off to get the crude compound 34. The crude waspassed through 100-200 mesh silica gel eluting the pure compound at 7-8%ethyl aceate in hexane as off white colored solid 34.

Step 2:

To a stirred solution of 34 (65 mg, 0.149 mmol) and compound 22 (21 mg,0.159 mmol) in acetonitrile (5 mL), degassed and purged with nitrogenfor 10 min, was added Cs₂CO₃ (95 mg, 0.289 mmol) and Pd(PPh3)₄ (8 mg,0.00724 mmol) and continued degassing and purging with nitrogen foranother 15 min. The resulting RM was heated to 85° C. overnight for 12hrs in a sealed tube. After completion of the SM monitored from TLC, theRM was cooled to rt, diluted with chloroform and the organic layer waspassed through celite bed. The organic layer was completely distilledoff to get the crude product 35. The crude product was passed through100-200 mesh silica gel eluting the pure compound 35 at 10-11% ethylacetate in hexane as off white solid compound.

Step 3:

To a stirred solution of compound 35 (60 mg, 0.120 mmol) in methanol (10mL) and water (5 mL) was added K₂CO₃ (33 mg, 0.241 mmol) and the RMheated to 60° C. for 12 hr. After completion of the SM, the solventswere removed, diluted with water and extracted with chloroform in twovolumes. The organic layer was dried over sodium sulphate. The crudematerial was passed through 100-200 mesh silica gel, eluting the thecompound at 28-30% ethyl acetate in hexane as eluent to get the paleyellow colored solid of compound 36.

¹H NMR (CDCl3) δ: 10.84 (s, 1H), 8.56 (d, 1H), 7.41 (d, 1H), 7.17 (m,2H), 7.03 (m, 2H), 6.97 (d, 1H), 6.61 (d, 1H), 3.21 (s, 3H); and MSm/z=341.8

Preparation of Example 73-(4-methoxyphenyl)-4-(thiophen-3-yl)-1H-pyrazolo[3,4-b]pyridine (40)

Step 1:

A stirred solution of3-bromo-4-chloro-1-tosyl-1H-pyrazolo[3,4-b]pyridine 8 (150 mg, 0.387mmol) and (4-methoxyphenyl)boronic acid 37 (59 mg, 0.387 mmol) inacetonitrile (5 mL) was degassed and purged with nitrogen for 10 min.Cesium carbonate (252 mg, 0.774 mmol) and Pd(dppf)Cl₂ (15 mg, 0.0193mmol) was added to the RM and degassed and purged with nitrogen againfor 15 min. The resulting RM was heated to 85° C. for 4 hr in a sealedtube. After completion of the reaction the crude RM was cooled to rt anddiluted with chloroform and filtered through celite bed. The organiclayer was completely distilled off. The obtained crude was passedthrough 100-200 mesh silica gel eluting the pure compound at 7-8% ethylaceate in hexane to provide off white colored solid of compound 38.

Step 2:

To a stirred solution of3-(4-methoxyphenyl)-4-(thiophen-3-yl)-1-tosyl-1H-pyrazolo[3,4-b]pyridine38 (75 mg, 0.181 mmol) and thiophen-3-ylboronic acid 22 (25 mg, 0.199mmol) in acetonitrile (5 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (0.118 g 0.363 mmol) and Pd(PPh3)₄ (10mg, 0.0090 mmol) and again degassed and purged with nitrogen for 15 min.Then the RM was heated to 85° C. overnight in a sealed tube. Aftercompletion of the SM, the RM was cooled to rt and diluted withchloroform and the organic layer was passed through celite bed. Theorganic layer was completely distilled off to get the crude product,which was passed through 100-200 mesh silica gel eluting the purecompound at 10-11% ethyl acetate in hexane giving an off white solid of3-(4-methoxyphenyl)-4-(thiophen-3-yl)-1-tosyl-1H-pyrazolo[3,4-b]pyridine39.

Step 3:

To a stirred solution of compound 39 (35 mg, 00758 mmol) in methanol (10mL) and water (5 mL) was added potassium carbonate (20 mg, 0.151 mmol)and the RM heated to 60° C. overnight. After completion of the SM, theRM was completely distilled off, diluted with water and extracted withchloroform twice. The organic layer was dried over sodium sulphate andthe solvent was completely distilled off to get the crude product, whichwas passed through 100-200 mesh silica gel eluting the compound at28-30% ethyl acetate in hexane as eluent to get the pale yellow coloredsolid of compound 40. ¹H NMR (CDCl₃) δ: 10.71 (s, 1H), 8.57 (d, 1H),7.18 (m, 4H), 7.09 (m, 1H), 6.92 (m, 1H), 6.74 (m, 1H), 3.81 (s, 3H) andMS m/z=307.9.

Preparation of Example 93-(2-fluorophenyl)-4-(thiophen-3-yl)-1H-pyrazolo[3,4-b]pyridine (44)

Step 1:

To a stirred solution of compound 8 (150 mg, 0.387 mmol) and 41 (54 mg,0.387 mmol) in acetonitrile (5 mL), degassed and purged with nitrogenfor 10 min, was added Cs₂CO₃ (253 mg 0.775 mmol) and Pd(dppf)Cl₂ (15 mg0.0193 mmol). The resulting RM was degassed, purged with nitrogen againfor 15 min again and heated to 85° C. for 4 hr in a sealed tube. Aftercompletion of the reaction, it was cooled to rt and diluted withchloroform and filtered through celite bed. The organic layer wascompletely distilled off to get the crude compound 38. The crude waspassed through 100-200 mesh silica gel eluting the pure compound at 7-8%ethyl aceate in hexane as off white colored solid 42.

Step 2:

To a stirred solution of 42 (100 mg, 0.248 mmol) and compound 22 (35 mg,0.273 mmol) in acetonitrile (5 mL), degassed and purged with nitrogenfor 10 min, was added Cs₂CO₃ (162 mg 0.497 mmol) and Pd(PPh3)₄ (14 mg,0.0124 mmol) and continued degassing and purging with nitrogen foranother 15 min. The resulting RM was heated to 85° C. overnight or 12hrs in a sealed tube. After completion of the SM monitored from TLC, theRM was cooled to rt and diluted with chloroform and the organic layerwas passed through celite bed. The organic layer was completelydistilled off to get the crude product 43. The crude product was passedthrough 100-200 mesh silica gel, eluting the pure compound 43 at 10-11%ethyl acetate in hexane as off white solid compound.

Step 3:

To a stirred solution of compound 43 (60 mg, 0.1334 mmol) in methanol(40 mL) and water (5 mL) was added K₂CO₃ (36.9 mg, 0.266 mmol) and theRM heated to 60° C. for 12 hr. After completion of the SM, the solventswere removed, diluted with water and extracted with chloroform in twovolumes. The organic layer was dried over sodium sulphate. The crudematerial was passed through 100-200 mesh silica gel eluting the thecompound at 28-30% ethyl acetate in hexane as eluent to get the paleyellow colored solid of compound 44. ¹H NMR (CDCl3) δ: 8.66 (d, 1H),7.31 (m, 1H), 7.20 (m, 1H), 7.19 (m, 2H), 7.02 (m, 1H), 6.93 (m, 2H),6.71 (m, 2H) and MS m/z=295.8.

Preparation of Intermediate 164-chloro-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (16)

Step 1:

4-chloro-1H-pyrrolo[2,3-b]pyridine (14) 1 g (6.55 mmol) in acetic acid(10 mL) cooled to 0° C. and was added N-chlorosuccinimide (0.875 g, 6.55mmol). The resulting RM was stirred for 4 hr at rt. After completion ofthe SM, the RM was quenched with ice water and extracted withdichloromethane (2×10 mL). The combined organic layer was dried oversodium sulphate, and the solvent evaporated to yield compound4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine 15.

Step 2:

To compound 15 (0.8 g, 2.87 mmol) in DMF (5 mL) cooled to 0° C. was addsodium hydride (0.138 g, 5.75 mmol, 2 eq) slowly under nitrogenatmosphere for 15 min followed by the addition of p-toluene sulfonylchloride (0.820 g, 4.31 mmol, 1.5 eq). The resulting RM was stirred for6 hr and after completion of the SMs from TLC; the RM was quenched withice cold water and extracted with chloroform. The combined organic layerwas washed with brine solution and the organic layer was dried oversodium sulphate. The solvents were removed to get the crude product,which was passed through through 100-200 mesh silica gel eluting thepure compound 16 at 6-7% ethyl acetate in hexane.

Preparation of Example 173-(2-methoxyphenyl)-4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine (52)

Step 1:

A stirred solution of compound 16 (150 mg, 0.347 mmol) and 49 (52.7 mg,0.347 mmol) in acetonitrile (5 mL) was degassed, purged with nitrogenfor 10 min and to which was added Cs₂CO₃ (151.1 mg, 0.485 mmol) andPd(dppf)Cl (14.1 mg, 0.017 mmol). The resulting RM was degassed, purgedwith nitrogen again for 15 min and was heated to 85° C. for 4 hr in asealed tube. After completion, the reaction was cooled to rt, dilutedwith chloroform, and filtered through celite bed. The organic layer wascompletely distilled off to get the crude compound 50. The crude waspassed through 100-200 mesh silica gel eluting the pure compound at 5%ethyl aceate in hexane as off white colored solid 50.

Step 2:

To a stirred solution of 50 (100 mg, 0.242 mmol) and compound 22 (34.1mg, 0.266 mmol) in acetonitrile (5 mL), degassed and purged withnitrogen for 10 min, was added Cs₂CO₃ (151.1 mg, 0.485 mmol) andPd(PPh3)₄ (14 mg, 0.0121 mmol) and continued degassing and purging withnitrogen for another 15 min. The resulting RM was heated to 85° C.overnight or 12 hrs in a sealed tube. After completion of the SMmonitored from TLC, the RM was cooled to rt and diluted with chloroformand the organic layer was passed through celite bed. The organic layerwas completely distilled off to get the crude product 51. The crudeproduct was passed through 100-200 mesh silica gel eluting the purecompound 51 at 4-5% ethyl acetate in hexane as off white solid compound.

Step 3:

To a stirred solution of compound 51 (50 mg, 0.108 mmol) in methanol (10mL) and water (5 mL) was added K₂CO₃ (29.9 mg, 0.217 mmol) and the RMheated to 60° C. for 12 hr. After completion of the SM, the solventswere removed, diluted with water and extracted with chloroform in twovolumes. The organic layer was dried over sodium sulphate. The crudematerial was passed through 100-200 mesh silica gel eluting the compoundat 28-30% ethyl acetate in hexane as eluent to get the pale yellowcolored solid of compound 48. ¹H NMR (CDCl3) δ: 9.00 (1-H), 8.33 (d,J=4.87 1-H), 7.35 (m, J=2.31 1-H), 7.23 (m, J=4.14 3-H), 7.11 (m, J=5.001-H), 7.04 (m, J=3.04 1-H), 6.90 (m, J=7.56 1-H), 6.56 (d, J=7.92 1-H),3.27 (3-H); and MS m/z=307.2.

Preparation of Example 183-(2,4-difluorophenyl)-4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine (56)

Step 1:

To a stirred solution of compound 16 (150 mg, 0.346 mmol) and 53 (54 mg,0.346 mmol) in acetonitrile (5 mL), degassed and purged with nitrogenfor 10 min, was added Cs₂CO₃ (282 mg, 0.866 mmol) and Pd(dppf)Cl (11 mg,0.013 mmol). The resulting RM was degassed, purged with nitrogen againfor 15 min and was heated to 85° C. for 4 hr in a sealed tube. Aftercompletion, the reaction was cooled to rt and diluted with chloroform 50mL and filtered through celite bed. The organic layer was completelydistilled off to get the crude compound 54. The crude was passed through100-200 mesh silica gel eluting the pure compound at 6% ethyl aceate inhexane as off white colored solid 54.

Step 2:

To a stirred solution of 54 (100 mg, 0.239 mmol) and compound 22 (30 mg,0.239 mmol) in acetonitrile (5 mL), degassed and purged with nitrogenfor 10 min, was added Cs₂CO₃ (194 mg, 0.597 mmol) and Pd(PPh3)₄ (11 mg,0.00956 mmol) and continued degassing and purging with nitrogen foranother 15 min. The resulting RM was heated to 85° C. overnight or 12 hrin a sealed tube. After completion of the SM monitored from TLC, the RMwas cooled to rt and diluted with chloroform and the organic layer waspassed through celite bed. The organic layer was completely distilledoff to get the crude product 55. The crude product was passed through100-200 mesh silica gel eluting the pure compound 55 at 10% ethylacetate in hexane as off white solid compound.

Step 3:

To a stirred solution of compound 55 (50 mg, 0.107 mmol) in methanol (10mL) and water (5 mL) was added K2CO3 (37 mg, 0.268 mmol) and the RMheated to 60° C. for 12 hr. After completion of the SM, the solventswere removed, diluted with water and extracted with chloroform in twovolumes. The organic layer was dried over sodium sulphate. The crudematerial was passed through 100-200 mesh silica gel eluting the thecompound at 28-30% ethyl acetate in hexane as eluent to get the paleyellow colored solid of compound 56.

1H NMR (CDCl3) δ: 9.43 (1-H), 8.37 (d, J=5.00 1-H), 7.40 (s, 1-H), 7.13(m, J=4.87 1-H), 7.00 (m, J=6.58 2-H) 6.96 (m, J=5.12 2-H) 6.87 (d,J=3.78 1-H) 6.60 (m, J=6.95 2-H); and MS m/z=312.8

Preparation of Example 19 4-(2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine(101)

Step 1:

To a stirred solution of tosylated 14 (100 mg, 0.326 mmol) and 99 (49.6mg, 0.326 mmol) in acetonitrile (6 mL), degassed and purged withnitrogen for 10 min, was added cesium carbonate (214 mg, 0.653 mmol) andPd(dppf)Cl₂ (18.8 mg, 0.0163 mmol), again degassed and purged withnitrogen for 15 min, and the RM heated to 85° C. overnight in a sealedtube. After completion of the SM, the RM was cooled to rt and dilutedwith chloroform and the organic layer was passed through celite bed. Theorganic layer was completely distilled off the solvent to get the crudeproduct which was passed through 100-200 mesh silica gel eluting thepure compound at 10-11% ethyl acetate in hexane as off white solidcompound 100.

Step 2:

To a stirred solution of 100 (45 mg, 0.119 mmol) in methanol (10 mL) andwater (5 mL) was added potassium carbonate (33 mg, 0.238 mmol) and theRM heated to 60° C. overnight. After completion of the SM, methanol wascompletely distilled off and the RM diluted with water and extractedwith chloroform twice. The organic layer was dried over sodium sulphateand completely distilled off to get the crude product which was passedthrough 100-200 mesh silica gel eluting the pre compound at 25-20% ethylacetate in hexane as eluent to get the pale yellow colored solidcompound 101. 1H NMR (CDCl3) δ: 9.43 (1-H), 8.31 (d, J=5.12 1-H), 7.46(m, J=5.85 2-H), 7.30 (d, J=3.53 1-H), 7.19 (d, J=5.00 1-H), 7.08 (m,J=7.43 2-H), 6.42 (d, J=3.53 1-H), 3.81 (s, 3-H).

Preparation of Example 20 4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine(66)

Step 1:

To a stirred solution of 14 (100 mg, 0.326 mmol) and 22 (50 mg 0.392mmol) in DME (5 mL) and water (1 mL), degassed and purged with nitrogenfor 10 min, was added cesium carbonate (214 mg, 0.653 mmol) andPd(pph₃)₄ (18.8 mg, 0.0163 mmol) and again degassed and purged withnitrogen for 15 min. Then the RM was heated to 85° C. overnight in asealed tube. After completion of the SM, the RM was cooltTed to rt anddiluted with chloroform and the organic layer passed through celite bed.The organic layer was completely distilled off the solvent to get thecrude product which was passed through 100-200 mesh silica gel, elutingthe pure compound 65 at 5% ethyl acetate in hexane as off white solid.

Step 2:

To a stirred solution of 65 (30 mg, 0.0847 mmol) in methanol (5 mL) andwater (1 mL) was added potassium carbonate (23.2 mg, 0.169 mmol) andheated to 60° C. overnight. After completion of the SM, methanol wascompletely distilled off and the RM diluted with water then extractedwith chloroform twice. The organic layer was dried over sodium sulphateand completely distilled off to get the crude product which was passedthrough 100-200 mesh silica gel eluting the pre compound at 25-20% ethylacetate in hexane as eluent to get the pale yellow colored solid 66. ¹HNMR (CDCl3) δ: 9.14 (1-H), 8.33 (M, J=5.00 1-H), 7.75 (m, J=1.58 1-H),7.56 (m, J=3.78 1-H) 7.49 (m, J=2.92 1-H), 7.38 (m, J=3.41 1-H), 7.22(m, J=2.56 1-H), 6.78 (m, J=1.95 1-H) and MS m/z=201.2.

Preparation of Example 214-(thiophen-3-yl)-3-(2-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine(90)

Step 1:

To a stirred solution of 16 (150 mg, 0.346 mmol) and 87 (65.8 mg, 0.346mmol) in acetonitrile (8 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (225.9 mg, 0.693 mmol) and Pd(dppf)Cl₂(14.1 mg, 0.0173 mmol), again degassed and purged with nitrogen againfor 15 min, and the RM heated to 85° C. for 4 hr in a sealed tube. Aftercompletion of the reaction the RM was cooled to rt and diluted withchloroform and filtered through celite bed. The organic layer wascompletely distilled off to get the crude which was passed through100-200 mesh silica gel eluting the pure compound at 7-8% ethyl aceatein hexane as off white colored solid compound 88.

Step 2:

To a stirred solution of 88 (80 mg, 0.177 mmol) and 22 (22 mg, 0.177mmol) in acetonitrile (6 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (115 mg, 0.354 momL) and Pd(PPh₃)₄ (10mg, 0.0088 mmol), again degassed and purged with nitrogen for 15 min,and the RM heated to 85° C. overnight in a sealed tube. After completionof the SM, the RM was cooled to rt and diluted with chloroform and theorganic layer was passed through celite bed. The organic layer wascompletely distilled off the solvent to get the crude product which waspassed through 100-200 mesh silica gel eluting the pure compound at10-11% ethyl acetate in hexane as off white solid compound 89.

Step 3:

To a stirred solution of 89 (40 mg, 0.0803 mmol) in methanol (15 mL) andwater (5 mL) was added potassium carbonate (22 mg, 0.160 mmol) and theRM heated to 60° C. overnight. After completion of the SM, methanol wascompletely distilled off and the RM diluted with water and extractedwith chloroform twice. The organic layer was dried over sodium sulphateand completely distilled off to get the crude product which was passedthrough 100-200 mesh silica gel eluting the pre compound at 25-20% ethylacetate in hexane as eluent to get the pale yellow colored solidcompound 90. ¹H NMR (CDCl3) δ: 9.21 (1-H), 8.35 (d, J=4.51 1-H), 7.64(d, J=7.8 1-H), 7.52 (s, J=9.39 1-H), 7.09 (m, J=4.26 2-H), 6.88 (m,J=12.19 3-H), 6.73 (d, J=4.63 1-H); and MS m/z=344.8.

Preparation of Example 223-(2-fluorophenyl)-4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine (60)

Step 1:

To a stirred solution of 16 (150 mg, 0.346 mmol) and 57 (48 mg, 0.346mmol) in acetonitrile (8 mL), degassed and purged with nitrogen for 10min, was add cesium carbonate (282 mg, 0.866 mmol) and Pd(dppf)Cl₂ (11mg, 0.0138 mmol), then degassed and purged with nitrogen again for 15min and the RM was heated to 85° C. for 4 hr in a sealed tube. Aftercompletion of the reaction the RM was cooled to rt and diluted withchloroform (50 mL) and filtered through celite bed. The organic layerwas completely distilled off to get the crude the crude was passedthrough 100-200 mesh silica gel eluting the pure compound 58 at 5% ethylaceate in hexane as off white colored solid.

Step 2:

To a stirred solution of 58 (100 mg, 0.249 m mol) and 22 (31 mg, 0.249mmol) in acetonitrile (7 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (203 mg, 0.623 m mol) and Pd(PPh₃)₄ (11mg, 0.0997 mmol), and again degassed and purged with nitrogen for 15min. Then the RM was heated to 85° C. overnight in a sealed tube. Aftercompletion of the SM the RM was cooled to rt and diluted with chloroform(50 mL) and the organic layer passed through celite bed. The organiclayer was completely distilled off the solvent to get the crude product,which was passed through 100-200 mesh silica gel eluting the purecompound 59 at 10-11% ethyl acetate in hexane as off white solid.

Step 3:

To a stirred solution of 59 (50 mg, 0.111 mmol) in methanol (7 mL) andwater (3 mL) was added potassium carbonate (38 mg, 0.278 m mol) andheated to 60° C. overnight. After completion of the SM, the RM wascompletely distilled off, diluted with water and extracted withchloroform (50 mL) twice. The organic layer was dried over sodiumsulphate and completely distilled off to get the crude product, whichwas passed through 100-200 mesh silica gel eluting the pre compound 60at 17% ethyl acetate in hexane as eluent to get the pale yellow coloredsolid. 1H NMR (CDCl3) δ: 9.08 (1-H), 8.36 (d, J=4.87 1-H), 7.42 (d,J=2.31 1-H), 7.28 (m, J=52.6 2-H), 7.17 (m, J=5.24 2-H) 7.13 (m, J=4.842-H) 7.05 (m, J=5.00 2-H) 6.94 (m, J=7.19 1-H), MS m/z=294.9.

Preparation of Example 233-(2-chloro-3-fluorophenyl)-4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine(98)

Step 1:

To a stirred solution of 16 (150 mg, 0.346 mmol) and 95 (60 mg, 0.346mmol) in acetonitrile (8 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (282 mg, 0.866 mmol) and Pd(dppf)Cl₂ (11mg, 0.0138 mmol), again degassed and purged with nitrogen for 15 min andthe RM heated to 85° C. for 4 hr in a sealed tube. After completion ofthe reaction the RM was cooled to rt and diluted with chloroform andfiltered through celite bed. The organic layer was completely distilledoff to get the crude which was passed through 100-200 mesh silica geleluting the pure compound at 7-8% ethyl aceate in hexane as off whitecolored solid 96.

Step 2:

To a stirred solution of 96 (0.229 mmol) and 22 (0.229 mmol) inacetonitrile (6 mL), degassed and purged with nitrogen for 10 min, wasadded cesium carbonate (0.574 mmol) and Pd(PPh₃)₄ (0.00968 mmol), againdegassed and purged with nitrogen for 15 min, and the RM heated to 85°C. overnight in a sealed tube. After completion of the SM, the RM wascooled to rt and diluted with chloroform and the organic layer waspassed through celite bed. The organic layer was completely distilledoff the solvent to get the crude product which was passed through100-200 mesh silica gel eluting the pure compound at 10-11% ethylacetate in hexane as off white solid 97.

Step 3:

To a stirred solution of 97 (30 mg, 0.0621 mmol) in methanol (10 mL) andwater (5 mL) was added potassium carbonate (17 mg, 0.124 mmol) and theRM heated to 60° C. overnight. After completion of the SM, methanol wascompletely distilled off and the RM diluted with water then extractedwith chloroform twice. The organic layer was dried over sodium sulphateand completely distilled off to get the crude product which was passedthrough 100-200 mesh silica gel eluting the pre compound at 25-20% ethylacetate in hexane as eluent to get the pale yellow colored solidcompound 98. 1H NMR (CDCl3) δ: 9.19 (1-H), 8.38 (d, J=4.75 1-H), 7.40(d, J=2.56 1-H), 7.13 (d, J=4.87 1-H), 7.01 (m, J=4.26 3-H) 6.85 (m,J=8.53 3-H); and MS m/z=328.8

Preparation of Example 243-(4-chloro-2-methoxyphenyl)-4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine(82)

Step 1:

To a stirred solution of 16 (150 mg, 0.347 mmol) and 79 (64.3 mg, 0.347mmol) in acetonitrile (7 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (228 mg, 0.694 mmol) and Pd(dppf)Cl₂(14.1 mg, 0.0173 mmol), again degassed and purged with nitrogen againfor 15 min and the RM was heated to 85° C. for 4 hr in a sealed tube.After completion of the reaction the RM was cooled to rt and dilutedwith chloroform and filtered through celite bed. The organic layer wascompletely distilled off to get the crude, which was passed through100-200 mesh silica gel eluting the pure compound at 7-8% ethyl aceatein hexane as off white colored solid compound 80.

Step 2:

To a stirred solution of 80 (100 mg, 0.224 mmol) and 22 (31.5 mg, 0.224mmol) in acetonitrile (7 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (147 mg, 0.448 mmol) and Pd(PPh₃)₄ (12.9mg, 0.011 mmol), again degassed and purged with nitrogen for 15 min, andthe RM heated to 85° C. overnight in a sealed tube. After completion ofthe SM, the RM was cooled to rt and diluted with chloroform and theorganic layer passed through celite bed. The organic layer wascompletely distilled off the solvent to get the crude product which waspassed through 100-200 mesh silica gel eluting the pure compound at10-11% ethyl acetate in hexane as off white solid compound 81.

Step 3:

To a stirred solution of 81 (60 mg, 0.121 mmol) in methanol (10 mL) andwater (5 mL) was added potassium carbonate (33 mg, 0.2424 mmol) andheated to 60° C. overnight. After completion of the SM, methanol wascompletely distilled off and the RM diluted with water then extractedwith chloroform twice. The organic layer was dried over sodium sulphateand completely distilled off to get the crude product which was passedthrough 100-200 mesh silica gel eluting the pre compound at 25-20% ethylacetate in hexane as eluent to get the pale yellow colored solidcompound 82. ¹H NMR (CDCl3) δ: 9.13 (1-H), 8.34 (d, J=4.87 1-H), 7.33(d, J=2.31 1-H), 7.09 (m, J=5.00 1-H), 6.88 (m, J=5.97 3-H), 6.55 (d,J=1.95 1-H) 3.28 (s, 3-H) and MS m/z=341.3.

Preparation of Example 253-(4-methoxyphenyl)-4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine (64)

Step 1:

To a stirred solution of 16 (150 mg, 0.346 mmol) and 61 (52 mg, 0.346mmol) in acetonitrile (7 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (282 mg 0.865 mmol) and Pd(dppf)Cl₂ (11mg, 0.013 mmol), again degassed and purged with nitrogen for 15 min andthe RM heated to 85° C. for 4 hr in a sealed tube. After completion ofthe reaction the RM was cooled to rt and diluted with chloroform (50 mL)and filtered through celite bed. The organic layer was completelydistilled off to get the crude, which was passed through 100-200 meshsilica gel eluting the pure compound 62 at 7-8% ethyl aceate in hexaneas off white colored solid.

Step 2:

To a stirred solution of 62 (100 mg, 0.242 mmol) and 22 (31 mg, 0.242mmol) in acetonitrile (6 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (197 mg, 0.605 mmol) and Pd(PPh₃)₄ (11mg 0.00908 mmol), and again degassed and purged with nitrogen for 15 minand heated to 85° C. overnight in a sealed tube. After completion of theSM the RM was cooled to rt and diluted with chloroform (50 mL) and theorganic layer was passed through celite bed. The organic layer wascompletely distilled off the solvent to get the crude product which waspassed through 100-200 mesh silica gel eluting the pure compound at10-11% ethyl acetate in hexane as off white solid compound 63.

Step 3:

To a stirred solution of 63 (40 mg 0.086 mmol) in methanol (7 mL) andwater (3 mL) was added potassium carbonate 30 mg (0.215 mmol) and heatedto 60° C. overnight. After completion of the SM, the RM was completelydistilled off, diluted with water and extracted with chloroform twice.The organic layer was dried over sodium sulphate and completelydistilled off to get the crude product which was passed through 100-200mesh silica gel eluting the pre compound at 20% ethyl acetate in hexaneas eluent to get the pale yellow colored solid. ¹H NMR (CDCl3) δ: 9.26(1H), 8.35 (d, J=4.87 1H), 7.33 (d, J=2.43 1H), 7.12 (d, J=4.87 1-H),7.07 (m, J=3.04 1-H) 6.95 (m, J=5.48 2-H) 6.93 (m, J=4.63 2-H) 6.87 (m,J=3.65 1-H), 6.67 (m, J=4.51 2-H), 3.79 (s 3-H); and MS m/z=307.2.

Preparation of Example 263-(2-ethoxyphenyl)-4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine (78)

Step 1:

To a stirred solution of 16 (150 mg, 0.347 mmol) and 75 (57.6 mg, 0.347mmol) in acetonitrile (7 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (228.1 mg, 0.694 mmol) and Pd(dppf)Cl₂(11 mg, 0.0138 mmol), again degassed and purged with nitrogen again for15 min and the RM heated to 85° C. for 4 hr in a sealed tube. Aftercompletion of the reaction the RM was cooled to rtand diluted withchloroform (50 mL) and filtered through celite bed. The organic layerwas completely distilled off to get the crude which was passed through100-200 mesh silica gel eluting the pure compound at 7-8% ethyl aceatein hexane as off white colored solid 76.

Step 2:

To a stirred solution of 76 (100 mg, 0.234 mmol) and 22 (30 mg, 0.234mmol) in acetonitrile (7 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (153 mg, 0.469 mmol) and Pd(PPh3)4 (11mg, 0.0093 mmol), again degassed and purged with nitrogen for 15 min andthe RM heated to 85° C. overnight in a sealed tube. After completion ofthe SM, the RM was cooled to rt and diluted with chloroform (50 mL) andthe organic layer was passed through celite bed. The organic layer wascompletely distilled off the solvent to get the crude product which waspassed through 100-200 mesh silica gel eluting the pure compound at10-11% ethyl acetate in hexane as off white solid compound 77.

Step 3:

To a stirred solution of 77 (30 mg 0.063 mmol) in methanol (5 mL) andwater (1 mL) was added potassium carbonate (21.8 mg, 0.158 mmol) and theRM heated to 60° C. overnight. After completion of the SM, methanol wascompletely distilled off and the RM diluted with water and extractedwith chloroform twice. The organic layer was dried over sodium sulphateand completely distilled off to get the crude product which was passedthrough 100-200 mesh silica gel eluting the pre compound at 25-20% ethylacetate in hexane as eluent to get the pale yellow colored solidcompound 78. ¹H NMR (CDCl3) δ: 9.10 (1-H), 8.33 (d, J=4.87 1-H), 7.36(d, J=2.31 1-H), 7.20 (m, J=5.61 2-H), 7.11 (d, J=5.00 1-H), 7.04 (m,J=2.92 1-H), 6.98 (m, J=6.70 1-H), 6.87 (m, J=7.31 2-H), 6.55 (d, J=8.171-H), 3.47 (q, J=6.95 2-H), 1.04 (t, J=6.95 3-H); and MS m/z=321.2.

Preparation of Example 273-(4-chloro-2-fluorophenyl)-4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine(94)

Step 1:

To a stirred solution of 16 (150 mg, 0.346 mmol) and 91 (60 mg, 0.346mmol) in acetonitrile (8 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (282 mg, 0.865 mmol) and Pd(dppf)Cl₂ (11mg, 0.0138 mmol), again degassed and purged with nitrogen again for 15min, and the RM heated to 85° C. for 4 hr in a sealed tube. Aftercompletion of the reaction the RM was cooled to rt and diluted withchloroform and filtered through celite bed. The organic layer wascompletely distilled off to get the crude which was passed through100-200 mesh silica gel eluting the pure compound at 7-8% ethyl aceatein hexane as off white colored solid compound 92.

Step 2:

To a stirred solution of 92 (100 mg, 0.229 mmol) and 2 (29 mg, 0.229mmol) in acetonitrile (6 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (186 mg, 0.574 mmol) and Pd(PPh₃)₄ (10mg, 0.0091 mmol), again degassed and purged with nitrogen for 15 min,and the RM heated to 85° C. overnight in a sealed tube. After completionof the SM, the RM was cooled to rt and diluted with chloroform and theorganic layer was passed through celite bed. The organic layer wascompletely distilled off the solvent to get the crude product which waspassed through 100-200 mesh silica gel eluting the pure compound at10-11% ethyl acetate in hexane as off white solid compound 93.

Step 3:

To a stirred solution of 93 (30 mg, 0.0621 mmol) in methanol (10 mL) andwater (5 mL) was added potassium carbonate (17 mg, 0.124 mmol) and theRM heated to 60° C. overnight. After completion of the SM, methanol wascompletely distilled off and the RM diluted with water and extractedwith chloroform twice. The organic layer was dried over sodium sulphateand completely distilled off to get the crude product which was passedthrough 100-200 mesh silica gel eluting the pre compound at 25-20% ethylacetate in hexane as eluent to get the pale yellow colored solidcompound 94. ¹H NMR (CDCl3) δ: 9.51 (1-H), 8.37 (d, J=4.75 1-H), 7.43(s, 1-H) 7.11 (m, J=8.29 2-H), 6.91 (m, J=8.29 5-H), and MS m/z=327.6.

Preparation of Example 283-(4-fluoro-2-methoxyphenyl)-4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine(86)

Step 1:

To a stirred solution of 16 (150 mg, 0.347 mmol) and 83 (59 mg, 0.347mmol) in acetonitrile (7 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (285 mg, 0.868 mmol) and Pd(dppf)Cl₂ (11mg, 0.0138 mmol), again degassed and purged with nitrogen for 15 min andthe RM heated to 85° C. for 4 hr in a sealed tube. After completion ofthe reaction the RM was cooled to rt and diluted with chloroform andfiltered through celite bed. The organic layer was completely distilledoff to get the crude which was passed through 100-200 mesh silica geleluting the pure compound at 7-8% ethyl aceate in hexane as off whitecolored solid compound 84.

Step 2:

To a stirred solution of 84 (110 mg, 0.255 mmol) and 22 (32 mg, 0.255mmol) in acetonitrile (7 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (209 mg, 0.638 mmol) and Pd(PPh₃)₄ (11mg, 0.0102 mmol), again degassed and purged with nitrogen for 15 min,and the RM heated to 85° C. overnight in a sealed tube. After completionof the SM, the RM was cooled to rt and diluted with chloroform and theorganic layer was passed through celite bed. The organic layer wascompletely distilled off the solvent to get the crude product which waspassed through 100-200 mesh silica gel eluting the pure compound at10-11% ethyl acetate in hexane as off white solid compound 85.

Step 3:

To a stirred solution of 85 (30 mg, 0.062 mmol) in methanol (10 mL) andwater (5 mL) was added potassium carbonate (17 mg, 0.125 mmol) and theRM heated to 60° C. overnight. After completion of the SM, methanol wascompletely distilled off and the RM diluted with water then extractedwith chloroform twice. The organic layer was dried over sodium sulphateand completely distilled off to get the crude product which was passedthrough 100-200 mesh silica gel eluting the pre compound at 25-20% ethylacetate in hexane as eluent to get the pale yellow colored solidcompound 86. ¹H NMR (CDCl3) δ: 9.11 (1-H), 8.33 (d, J=311 1-H), 7.32 (s,2-H), 7.11 (m, J=13.17 3-H), 6.90 (d, J=4.50 2-H), 6.61 (t, J=6.09 1-H),6.30 (d, J=9.14 1-H) 3.20 (s, 3-H) and MS m/z=324.8

Preparation of Example 294-chloro-3-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine (103)

Step 1:

To a stirred solution of 16 (150 mg, 0.347 mmol) and 22 (44 mg, 0.347mmol) in acetonitrile (7 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (226 mg, 0.866 mmol) and Pd(dppf)Cl₂ (14mg, 0.0173 mmol), again degassed and purged with nitrogen for 15 min andthe RM heated to 85° C. for 4 hr in a sealed tube. After completion ofthe reaction the RM was cooled to rt and diluted with chloroform andfiltered through celite bed. The organic layer was completely distilledoff to get the crude which was passed through 100-200 mesh silica geleluting the pure compound at 7-8% ethyl aceate in hexane as off whitecolored solid compound 102.

Step 2:

To a stirred solution of 102 (70 mg, 0.180 mmol) in methanol (15 mL) andwater (5 mL) was added potassium carbonate (49 mg, 0.360 mmol) and theRM heated to 60° C. overnight. After completion of the SM, methanol wascompletely distilled and the RM diluted with water then extracted withchloroform twice. The organic layer was dried over sodium sulphate andcompletely distilled off to get the crude product which was passedthrough 100-200 mesh silica gel eluting the pre compound at 25-20% ethylacetate in hexane as eluent to get the pale yellow colored solidcompound 103. ¹H NMR (CDCl3) δ: 9.78 (1-H), 8.21 (d, J=5.12 1H), 7.39(d, J=2.31 1-H), 7.35 (m, J=3.04 2-H), 7.29 (m, J=2.92 1-H), 7.13 (d,J=5.12 1-H); and MS m/z=234.8.

Preparation of Example 304-(2-methoxyphenyl)-3-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine (106)

Step 1:

To a stirred solution of 16 (150 mg, 0.347 mmol) and 22 (44 mg, 0.347mmol) in acetonitrile (7 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (226 mg, 0.866 mmol) and Pd(dppf)Cl₂ (14mg, 0.0173 mmol), again degassed and purged with nitrogen for 15 min andthe RM heated to 85° C. for 4 hr in a sealed tube. After completion ofthe reaction the RM was cooled to rt and diluted with chloroform andfiltered through celite bed. The organic layer was completely distilledoff to get the crude which was passed through 100-200 mesh silica geleluting the pure compound at 7-8% ethyl aceate in hexane as off whitecolored solid compound 104.

Step 2:

To a stirred solution of 104 (100 mg, 0.257 mmol) and 20 (39.1 mg, 0.257mmol) in acetonitrile (6 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (167.4 mg, 0.513 mmol) and Pd(PPh₃)(14.8 mg, 0.0128 mmol), again degassed and purged with nitrogen for 15min, and the RM heated to 85° C. overnight in a sealed tube. Aftercompletion of the SM, the RM was cooled to rt and diluted withchloroform and the organic layer was passed through celite bed. Theorganic layer was completely distilled off the solvent to get the crudeproduct which was passed through 100-200 mesh silica gel eluting thepure compound at 10-11% ethyl acetate in hexane as off white solidcompound 105.

Step 3:

To a stirred solution of 105 (45 mg, 0.0978 mmol) in methanol (15 mL)and water (5 mL) was added potassium carbonate (26.9 mg, 0.1949 mmol)and the RM heated to 60° C. overnight. After completion of the SM,methanol was completely distilled off and the RM diluted with water andextracted with chloroform twice. The organic layer was dried over sodiumsulphate and completely distilled off to get the crude product which waspassed through 100-200 mesh silica gel eluting the pre compound at25-20% ethyl acetate in hexane as eluent to get the pale yellow coloredsolid compound 106. 1H NMR (CDCl3) δ: 8.95 (s, 1H), 8.38 (d, 1H), 7.34(d, 1H), 7.30 (m, 1H), 7.23 (d, 1H), 7.06 (d, 1H), 6.96 (m, 2H), 6.62(m, 2H), 6.51 (m, 1H) 3.29 (s, 3H); and MS m/z=306.8.

Preparation of Example 363-(2-methoxypyridin-3-yl)-4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine(70, ARN-3088)

Step 1:

To a stirred solution of 16 (150 mg, 0.346 mmol) and 67 (53 mg 0.346mmol) in acetonitrile (6 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate 225 mg, (0.693 mmol) and Pd(dppf)Cl₂ (14mg 0.0173 mmol), again degassed and purged with nitrogen again for 15min and the RM was heated to 85° C. for 4 hr in a sealed tube. Aftercompletion of the reaction the RM was cooled to rt and diluted withchloroform (50 mL) and filtered through celite bed. The organic layerwas completely distilled off to get the crude which was passed through100-200 mesh silica gel eluting the pure compound 68 at 7-8% ethylaceate in hexane as off white colored solid.

Step 2:

To a stirred solution of 68 (130 mg, 0.314 mmol) and 22 (45 mg 0.345mmol) in acetonitrile (7 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (205 mg, 0.628 mmol) and Pd(pph3)4 (18mg, 0.0157 mmol), again degassed and purged with nitrogen for 15 min,and heated to 85° C. overnight in a sealed tube. After completion of theSM, the RM was cooled to rt and diluted with chloroform (50 mL) and theorganic layer was passed through celite bed. The organic layer wascompletely distilled off the solvent to get the crude product which waspassed through 100-200 mesh silica gel eluting the pure compound 69 at10-11% ethyl acetate in hexane as off white solid.

Step 3:

To a stirred solution of 69 (50 mg, 0.108 mmol) in methanol (10 mL) andwater (5 mL) was added potassium carbonate (30 mg, 0.216 m mol) andheated to 60° C. overnight. After completion of the SM, methanol wascompletely distilled off and the RM diluted with water and extractedwith chloroform twice. The organic layer was dried over sodium sulphateand completely distilled off to get the crude product which was passedthrough 100-200 mesh silica gel eluting the pre compound at 25-20% ethylacetate in hexane as eluent to get the pale yellow colored solidcompound 70. 1H NMR (CDCl3) δ: 9.05 (1-H), 8.35 (d, J=4.87 1-H), 8.04(m, j=3.04 1-H), 7.41 (m, J=1.95 2-H), 7.12 (d, J=4.87 1-H), 7.07 (m,J=3.04 1-H), 6.90 (m, J=5.36 2-H), 6.79 (m, J=5.12 1-H), 3.49 (s, 1-H),and MS m/z=307.9.

Preparation of Example 374-(3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2-yl)morpholine(74)

Step 1:

To a stirred solution of 16 (150 mg, 0.346 mmol) and 71 (72 mg, 0.346mmol) in acetonitrile (6 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (225 mg, 0.693 mmol) and Pd(dppf)Cl₂ (14mg, 0.0173 mmol), again degassed and purged with nitrogen again for 15min and heated to 85° C. for 4 hr in a sealed tube. After completion ofthe reaction, the RM was cooled to rt and diluted with chloroform (50mL) and filtered through celite bed. The organic layer was completelydistilled off to get the crude which was passed through 100-200 meshsilica gel eluting the pure compound at 7-8% ethyl aceate in hexane asoff white colored solid compound 72.

Step 2:

To a stirred solution of 72 (100 mg, 0.213 mmol) and 22 (30 mg 0.345mmol) in acetonitrile (7 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (139 mg, 0.426 mmol) and Pd(PPh₃)₄ (12mg, 0.0106 mmol), again degassed and purged with nitrogen for 15 min,and heated to 85° C. overnight in a sealed tube. After completion of theSM, the RM was cooled to rt and diluted with chloroform (50 mL) and theorganic layer was passed through celite bed. The organic layer wascompletely distilled off the solvent to get the crude product which waspassed through 100-200 mesh silica gel eluting the pure compound at10-11% ethyl acetate in hexane as off white solid compound 73.

Step 3:

To a stirred solution of 73 (40 mg, 0.0774 mmol) in methanol (10 mL) andwater (5 mL) was added potassium carbonate (22 mg, 0.154 mmol), thenheated to 60° C. overnight. After completion of the SM, methanol wascompletely distilled off and the RM diluted with water then extractedwith chloroform twice. The organic layer was dried over sodium sulphateand completely distilled off to get the crude product which was passedthrough 100-200 mesh silica gel eluting the pre compound at 25-20% ethylacetate in hexane as eluent to get the pale yellow colored solidcompound 74. 1H NMR (CDCl3) δ: 11.98 (1-H), 8.28 (d, J=4.87 1-H), 8.08(M, J=2.92 1-H), 7.61 (d, J=2.56 1-H), 7.55 (m, J=5.48 1-H), 7.24 (m,J=2.92 1-H) 7.14 (d, J=4.87 1-H), 6.94 (m, J=4.87 3-H), 3.33 (s, 4-H),3.07 (s, 4-H) and MS m/z=362.9.

Preparation of Example 473-(3-chlorophenyl)-4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine (110,ARN-3111)

Step 1:

To a stirred solution of 16 (150 mg, 0.343 mmol) and 107 (88 mg, 0.343mmol) in acetonitrile (7 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (223 mg, 0.686 mmol) and Pd(dppf)Cl₂ (14mg, 0.0171 mmol), again degassed and purged with nitrogen for 15 min,and the RM heated to 85° C. for 4 hr in a sealed tube. After completionof the reaction the RM was cooled to rt, diluted with chloroform andfiltered through celite bed. The organic layer was completely distilledoff to get the crude which was passed through 100-200 mesh silica geleluting the pure compound at 7-8% ethyl aceate in hexane as off whitecolored solid compound 108.

Step 2:

To a stirred solution of 108 (100 mg, 0.239 mmol) and 22 (31 mg, 0.240mmol) in acetonitrile (7 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (155 mg, 0.475 mmol) and Pd(PPh₃)₄ (10mg, 0.019 mmol), again degassed and purged with nitrogen for 15 min, andthe RM heated to 85° C. overnight in a sealed tube. After completion ofthe SM, the RM was cooled to rt, diluted with chloroform and the organiclayer passed through celite bed. The organic layer was completelydistilled off the solvent to get the crude product which was passedthrough 100-200 mesh silica gel eluting the pure compound 109 at 10-11%ethyl acetate in hexane as off white solid.

Step 3:

To a stirred solution of 109 (45 mg, 0.097 mmol) in methanol (10 mL) andwater (10 mL) was added potassium carbonate (40 mg, 0.29 mmol) and theRM heated to 60° C. overnight. After completion of the SM, methanol wascompletely distilled off and the RM diluted with water, then extractedwith chloroform twice. The organic layer was dried over sodium sulphateand completely distilled off to get the crude product, which was passedthrough 100-200 mesh silica gel eluting the pre compound at 25-20% ethylacetate in hexane as eluent to get the pale yellow colored solidcompound 110. ¹H NMR (CDCl3) δ: 9.18 (s, 1H), 8.41 (m, 1H), 7.39 (m,1H), 7.13 (m, 6H), 6.89 (m, 2H), and MS m/z=310.8.

Preparation of Example 863-(2,4-dimethoxyphenyl)-4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine(114)

Step 1:

To a stirred solution of 16 (150 mg, 0.347 mmol) and 111 (59 mg, 0.347mmol) in acetonitrile (7 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (228 mg, 0.694 mmol) and Pd(dppf)Cl₂ (14mg, 0.0173 mmol), again degassed and purged with nitrogen for 15 min andthe RM heated to 85° C. for 4 hr in a sealed tube. After completion ofthe reaction the RM was cooled to rt and diluted with chloroform andfiltered through celite bed. The organic layer was completely distilledoff to get the crude product, which was passed through 100-200 meshsilica gel eluting the pure compound at 10-11% ethyl aceate in hexane asoff white colored solid compound 112.

Step 2:

To a stirred solution of 112 (100 mg, 0.339 mmol) and 22 (44 mg, 0.339mmol) in acetonitrile (7 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (229 mg, 0.678 mmol) and Pd(PPh₃)₄ (20mg, 0.017 mmol), and again degassed and purged with nitrogen for 15 min.Then the RM was heated to 85° C. overnight in a sealed tube. Aftercompletion of the SM, the RM was cooled to rt and diluted withchloroform and the organic layer was passed through celite bed. Theorganic layer was completely distilled off to get the crude product,which was passed through 100-200 mesh silica gel eluting the purecompound in 11-13% ethyl acetate and hexane as off white solid compound113.

Step 3:

To a stirred solution of 113 (40 mg, 0.0816 mmol) in methanol (10 mL)and water (10 mL) was added potassium carbonate (28 mg, 0.204 mmol). TheRM was heated to 60° C. overnight. After completion of the SMs, thesolvent methanol was completely distilled off and diluted with waterextracted with chloroform twice. The organic layer was dried over sodiumsulphate and the solvents removed to get the crude product, which waspassed through 100-200 mesh silica gel eluting the compound at 25-20%ethyl acetate in hexane as eluent to get the pale yellow colored solidcompound 114. ¹H NMR (CDCl₃) δ: 9.06 (s, 1H), 8.32 (d, 1H), 7.30 (d,1H), 7.12 (m, 2H), 7.07 (m, 1H), 6.94 (m, 1H), 6.90 (m, 1H), 6.44 (m,1H), 6.16 (d, 1H), 3.82 (s, 3H), 3.24 (s, 3H). MS/Mz: 337.2.

Preparation of Example 873-(2,4-difluorophenyl)-4-(thiophen-3-yl)-1H-pyrazolo[3,4-b]pyridine (48)

Step 1:

To a stirred solution of compound 8 (150 mg, 0.387 mmol) and 45 (66 mg,0.387 mmol) in acetonitrile (5 mL), degassed and purged with nitrogenfor 10 min, was added Cs₂CO₃ (253 mg 0.775 mmol) and Pd(dppf)Cl₂ (15 mg0.0193 mmol). The resulting RM was degassed, purged with nitrogen againfor 15 min and heated to 85° C. for 4 hr in a sealed tube. Aftercompletion of the reaction, it was cooled to rt and diluted withchloroform and filtered through celite bed. The organic layer wascompletely distilled off to get the crude compound 46. The crude waspassed through 100-200 mesh silica gel, eluting the pure compound at7-8% ethyl aceate in hexane as off white colored solid 46.

Step 2:

To a stirred solution of 46 (60 mg, 0.2135 mmol) and compound 22 (20 mg,0.148 mmol) in acetonitrile (5 mL), degassed and purged with nitrogenfor 10 min, was added Cs₂CO₃ (88 mg, 0.79 mmol) and Pd(PPh3)₄ (8 mg,0.00675 mmol) and continued degassing and purging with nitrogen foranother 15 min. The resulting RM was heated to 85° C. overnight or 12hrs in a sealed tube. After completion of the SM monitored from TLC, theRM was cooled to rt and diluted with chloroform and the organic layerwas passed through celite bed. The organic layer was completelydistilled off to get the crude product 47. The crude product was passedthrough 100-200 mesh silica gel eluting the pure compound 47 at 10-11%ethyl acetate in hexane as off white solid compound.

Step 3:

To a stirred solution of compound 47 (40 mg, 0.0813 mmol) in methanol(10 mL) and water (5 mL) was added K₂CO₃ (22 mg, 0.162 mmol) and heatedto 60° C. for 12 hr. After completion of the SM, the solvents wereremoved, diluted with water and extracted with chloroform in twovolumes. The organic layer was dried over sodium sulphate. The crudematerial was passed through 100-200 mesh silica gel eluting the thecompound at 28-30% ethyl acetate in hexane as eluent to get the paleyellow colored solid of compound 48. ¹H NMR (CDCl3) δ: 10.65 (s, 1H),8.54 (d, 1H), 7.52 (s, 1H), 7.39 (m, 2H), 7.13 (m, 2H), 6.55 (m, 1H),6.19 (d, 1H), 3.85 (s, 3H), 3.18 (s, 3H) and MS m/z=338.3

Preparation of Example 90N,N-dimethyl-3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzenesulfonamide(177)

Step 1

To a stirred solution of 115 (150 mg, 0.347 mmol) and 174 (79 mg, 0.347mmol) in acetonitrile (10 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (226 mg 0.694 mmol) and Pd(dppf)Cl₂ (14mg, 0.017 mmol), again degassed and purged with nitrogen for 15 min andthe RM heated to 85° C. for 4 hr in a sealed tube. After completion ofthe reaction, the RM was cooled to rt and diluted with chloroform andfiltered through celite bed. The organic layer was completely distilledoff to get the crude, which was passed through 100-200 mesh silica geleluting the pure compound at 5% ethyl aceate in hexane as off whitecolored solid compound 175.

Step 2

To a stirred solution of 175 (100 mg, 0.204 mmol) and 22 (26 mg, 0.204mmol) in acetonitrile (10 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (133 mg, 0.408 mmol) and Pd(dppf)Cl₂ (8mg, 0.0102 mmol), again degassed and purged with nitrogen for 15 min andthe RM heated to 85° C. for 4 hr in a sealed tube. After completion ofthe reaction, the RM was cooled to rt and diluted with chloroform andfiltered through celite bed. The organic layer was completely distilledoff to get the crude product, which was passed through 100-200 meshsilica gel eluting the pure compound at 5% ethyl aceate in hexane as offwhite colored solid compound 176.

Step 3

To a stirred solution of 177 (45 mg, 0.0773 mmol) in methanol (15 mL)was added water (10 mL) and potassium carbonate (26 mg 0.193 mmol) andthe RM heated to 60° C. overnight after completion of the SM, the RM wascompletely distilled off and diluted with water and extract withchloroform twice. The organic layer was dried over sodium sulphate andcompletely distilled off to get the crude product, which was passedthrough 100-200 mesh silica gel eluting the pre compound at 28-30% ethylacetate in hexane as eluent to get the pale yellow colored solidcompound 177. ¹H NMR (CDCl₃) δ: 9.09 (1-H), 8.39 (d, J=4.75 1H), 7.55(m, J=6.9 3-H), 7.52 (m, J=14.39 1-H), 7.20 (d, J=7.80 2-H), 7.16 (m,J=4.87 2-H), 7.07 (m, J=11.58 1-H), 6.84 (d, J=4.87 1-H), 2.67 (6-H) andMS m/z=383.2 (M+H)⁺.

Preparation of Example 91N-(tert-butyl)-N-methyl-3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzenesulfonamide(181)

Step 1:

To a stirred solution of 16 (150 mg, 0.347 mmol) and 178 (94 mg, 0.347mmol) in acetonitrile (5 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (228 mg, 0.694 mmol) and Pd(dppf)Cl₂(14.1 mg, 0.0173 mmol), again degassed and purged with nitrogen for 15min and the RM heated to 85° C. for 4 hr in a sealed tube. Aftercompletion of the reaction, the RM was cooled to rt and diluted withchloroform and filtered through celite bed. The organic layer wascompletely distilled off to get the crude product, which was passedthrough 100-200 mesh silica gel eluting the pure compound at 5% ethylaceate in hexane as off white colored solid compound 179.

Step 2:

To a stirred solution of 179 (80 mg, 0.150 mmol) and 22 (21 mg, 0.165mmol) in acetonitrile (5 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate and Pd(dppf)Cl₂, again degassed andpurged with nitrogen for 15 min and the RM heated to 85° C. for 4 hr ina sealed tube. After completion of the reaction the RM was cooled to rtand diluted with chloroform and filtered through celite bed. The organiclayer was completely distilled off to get the crude, which was passedthrough 100-200 mesh silica gel eluting the pure compound at 5% ethylaceate in hexane as off white colored solid compound 180.

Step 3:

To a stirred solution of 180 (80 mg, 0.138 mmol) in methanol (15 mL) wasadded water (10 mL) and potassium carbonate (47 mg 0.345 mmol) and theRM heated to 60° C. overnight. After completion of the SM, the RM wascompletely distilled off and diluted with water and extract withchloroform twice. The organic layer was dried over sodium sulphate andcompletely distilled off to get the crude product, which was passedthrough 100-200 mesh silica gel eluting the pre compound at 28-30% ethylacetate in hexane as eluent to get the pale yellow colored solidcompound 181. ¹H NMR (CDCl₃) δ: 12.17 (1H), 8.31 (d, J=4.26 1H), 7.72(s, 1-H), 7.52 (m, J=8.04 2-H), 6.95 (m, J=7.56, 6H), 2.85 (s, 3H), 1.25(s, 9H), MS m/z=426.3 (M+H)⁺.

Preparation of Example 92N,N-dimethyl-4-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzenesulfonamide(185)

Step 1:

To a stirred solution of 16 (150 mg, 0.347 mmol) and 182 (79.5 mg, 0.347mmol) in acetonitrile (5 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (226 mg, 0.695 mmol) and Pd(dppf)Cl₂ (14mg, 0.0173 mmol), again degassed and purged with nitrogen for 15 min andthe RM heated to 85° C. for 4 hr in a sealed tube. After completion ofthe reaction the RM was cooled to rt and diluted with chloroform andfiltered through celite bed. The organic layer was completely distilledoff to get the crude product, which was passed through 100-200 meshsilica gel eluting the pure compound at 5% ethyl aceate in hexane as offwhite colored solid compound 183.

Step 2:

To a stirred solution of 183 (120 mg, 0.255 mmol) and 22 (49 mg, 0.384mmol) in acetonitrile (5 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (166 mg, 0.512 mmol) and Pd(dppf)Cl₂ (10mg, 0.0127 mmol), again degassed and purged with nitrogen for 15 min andthe RM heated to 85° C. for 4 hr in a sealed tube. After completion ofthe reaction the RM was cooled to rt and diluted with chloroform andfiltered through celite bed. The organic layer was completely distilledoff to get the crude product, which was passed through 100-200 meshsilica gel eluting the pure compound at 5% ethyl aceate in hexane as offwhite colored solid compound 184.

Step 3:

To a stirred solution of 184 (40 mg, 0.0744 mmol) in methanol (15 mL)was added water (10 mL) and potassium carbonate (25 mg, 0.186 mmol) andthe RM heated to 60° C. overnight. After completion of the SM, the RMwas completely distilled off and diluted with water and extract withchloroform twice. The organic layer was dried over sodium sulphate andcompletely distilled off to get the crude product, which was passedthrough 100-200 mesh silica gel eluting the pre compound at 28-30% ethylacetate in hexane as eluent to get the pale yellow colored solidcompound 185. ¹H NMR (CDCl₃) δ: 9.25 (1-H), 8.41 (d, J=4.87 1-H), 7.51(m, J=8.4 2-H), 7.45 (d, J=2.56 1-H), 7.17 (m, J=5.00 3-H), 7.10 (m,J=3.04 1-H), 6.98 (m, J=4.14 1-H), 6.88 (m, J=4.87 1-H), 2.72 (S, 6-H)and MS m/z=383.9 (M+H)⁺.

Preparation of Example 93N,N-diethyl-3-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzenesulfonamide(189)

Step 1:

To a stirred solution of 16 (150 mg, 0.347 mmol) and 186 (89 mg, 0.347mmol) in acetonitrile (5 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (226 mg, 0.694 mmol) and Pd(dppf)Cl₂ (14mg, 0.0173 mmol), again degassed and purged with nitrogen for 15 min andthe RM heated to 85° C. for 4 hr in a sealed tube. After completion ofthe reaction the RM was cooled to rt and diluted with chloroform andfiltered through celite bed. The organic layer was completely distilledoff to get the crude product, which was passed through 100-200 meshsilica gel eluting the pure compound at 5% ethyl aceate in hexane as offwhite colored solid compound 187.

Step 2:

To a stirred solution of 187 (100 mg, 0.198 mmol) and 22 (64 mg, 0.198mmol) in acetonitrile (5 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (129 mg, 0.396 mmol) and Pd(dppf)Cl₂ (6mg, 0.0079 mmol), again degassed and purged with nitrogen for 15 min andthe RM heated to 85° C. for 4 hr in a sealed tube. After completion ofthe reaction the RM was cooled to rt and diluted with chloroform andfiltered through celite bed. The organic layer was completely distilledoff to get the crude product, which was passed through 100-200 meshsilica gel eluting the pure compound at 5% ethyl aceate in hexane as offwhite colored solid compound 188.

Step 3:

To a stirred solution of 188 (60 mg, 0.1087 mmol) in methanol (10 mL)was added water (5 mL) and potassium carbonate (45 mg, 0.326 mmol) andthe RM heated to 60° C. overnight. After completion of the SM, the RMwas completely distilled off and diluted with water and extract withchloroform twice. The organic layer was dried over sodium sulphate andcompletely distilled off to get the crude product, which was passedthrough 100-200 mesh silica gel eluting the pre compound at 28-30% ethylacetate in hexane as eluent to get the pale yellow colored solidcompound 189. ¹H NMR (CDCl₃) δ: 9.45 (1-H), 8.40 (S, 1-H), 7.68 (S,1-H), 7.57 (d, J=43.1, 1-H), 7.43 (S, 1-H), 7.17 (m, J=42.56, 2-H), 6.98(m, J=18.41, 3-H), 6.85 (d, J=52.1, 1-H), 3.21 (m, J=6.95, 4-H), 1.13(S, 6-H) and MS m/z=412.3 (M+H)⁺.

Preparation of Example 94N,N-dimethyl-2-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzenesulfonamide(193)

Step 1:

To a stirred solution of 16 (150 mg, 0.347 mmol) and 190 (79 mg, 0.347mmol) in acetonitrile (5 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (226 mg, 0.694 mmol) and Pd(dppf)Cl₂ (14mg, 0.0173 mmol), again degassed and purged with nitrogen for 15 min andthe RM heated to 85° C. for 4 hr in a sealed tube. After completion ofthe reaction the RM was cooled to rt and diluted with chloroform andfiltered through celite bed. The organic layer was completely distilledoff to get the crude, which was passed through 100-200 mesh silica geleluting the pure compound at 5% ethyl aceate in hexane as off whitecolored solid compound 190.

Step 2:

To a stirred solution of 191 (100 mg, 0.204 mmol) and 22 (26 mg, 0.204mmol) in acetonitrile (5 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (134 mg, 0.408 mmol) and Pd(dppf)Cl₂ (8mg, 0.0101 mmol), again degassed and purged with nitrogen for 15 min andthe RM heated to 85° C. for 4 hr in a sealed tube. After completion ofthe reaction the RM was cooled to rt and diluted with chloroform andfiltered through celite bed. The organic layer was completely distilledoff to get the crude, which was passed through 100-200 mesh silica geleluting the pure compound at 5% ethyl aceate in hexane as off whitecolored solid compound 192.

Step 3:

To a stirred solution of 192 (50 mg, 0.0931 mmol) in methanol (15 mL)was added water (10 mL) and potassium carbonate (32 mg, 0.232 mmol) andthe RM heated to 60° C. overnight. After completion of the SM, the RMwas completely distilled off and diluted with water and extract withchloroform twice. The organic layer was dried over sodium sulphate andcompletely distilled off to get the crude product, which was passedthrough 100-200 mesh silica gel eluting the pre compound at 28-30% ethylacetate in hexane as eluent to get the pale yellow colored solidcompound 193. ¹H NMR (CDCl3) δ: 9.41 (S, 1-H), 8.36 (d, J=5, 1-H), 7.85(dd, J=6.7, 1-H), 7.6 (d, J=2.56, 1-H), 7.28 (m, J=6.21, 1-H), 7.12 (m,J=6.34, 2-H), 6.94 (m, J=2.92, 2-H), 6.89 (dd, J=6.34, 1-H), 6.81 (m,J=2.43, 1-H, 2.66 (S, 6-H) and MS m/z=384.2 (M+H)⁺.

Preparation of Example 95N,N-diethyl-2-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzenesulfonamide(197)

Step 1:

To a stirred solution of 16 (150 mg, 0.347 mmol) and 194 (89 mg, 0.347mmol) in acetonitrile (5 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (226 mg, 0.694 mmol) and Pd(dppf)Cl₂ (14mg, 0.0173 mmol), again degassed and purged with nitrogen for 15 min andthe RM heated to 85° C. for 4 hr in a sealed tube. After completion ofthe reaction the RM was cooled to rt and diluted with chloroform andfiltered through celite bed. The organic layer was completely distilledoff to get the crude product, which was passed through 100-200 meshsilica gel eluting the pure compound at 5% ethyl aceate in hexane as offwhite colored solid compound 195.

Step 2:

To a stirred solution of 195 (100 mg, 0.198 mmol) and 22 (64 mg, 0.198mmol) in acetonitrile (5 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (129 mg, 0.396 mmol) and Pd(dppf)Cl₂ (6mg, 0.0079 mmol), again degassed and purged with nitrogen for 15 min andthe RM heated to 85° C. for 4 hr in a sealed tube. After completion ofthe reaction the RM was cooled to rt and diluted with chloroform andfiltered through celite bed. The organic layer was completely distilledoff to get the crude product, which was passed through 100-200 meshsilica gel eluting the pure compound at 5% ethyl aceate in hexane as offwhite colored solid compound 196.

Step 3:

To a stirred solution of 196 (60 mg, 0.108 mmol) in methanol (10 mL) wasadded water (5 mL) and potassium carbonate (45 mg, 0.326 mmol) and theRM heated to 60° C. overnight. After completion of the SM, the RM wascompletely distilled off and diluted with water and extract withchloroform twice. The organic layer was dried over sodium sulphate andcompletely distilled off to get the crude product, which was passedthrough 100-200 mesh silica gel eluting the pre compound at 28-30% ethylacetate in hexane as eluent to get the pale yellow colored solidcompound 197. ¹H NMR (CDCl3) δ: 9.00 (1H), 8.36 (d, J=5.0, 1-H), 7.78(dd, J=7.92, 1H), 7.63 (d, J=63.04, 1H), 7.23 (m, J=7.92, 1-H), 7.07 (m,J=8.04 2H), 6.96 (m, J=1.7, 1H), 6.92 (m, J=2.92 1H), 6.83 (m, J=6.46,2H), 3.2 (m, J=7.07, 4H), 1.11 (m, J=7.07, 6-H) and MS m/z=412.7 (M+H)⁺.

Preparation of Example 963-(4-(azetidin-1-ylsulfonyl)phenyl)-4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine(201)

Step 1:

To a stirred solution of 16 (150 mg, 0.347 mmol) and 198 (83 mg, 0.347mmol) in acetonitrile (5 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (226 mg) and Pd(dppf)Cl₂ (14 mg, 0.0176mmol), again degassed and purged with nitrogen for 15 min and the RMheated to 85° C. for 4 hr in a sealed tube. After completion of thereaction the RM was cooled to rt and diluted with chloroform andfiltered through celite bed the organic layer was completely distilledoff to get the crude product, which was passed through 100-200 meshsilica gel eluting the pure compound at 5% ethyl aceate in hexane as offwhite colored solid compound 199.

Step 2:

To a stirred solution of 199 (100 mg, 0.204 mmol) and 22 (26 mg, 0.204mmol) in acetonitrile (5 mL) degassed and purged with nitrogen for 10min, was added cesium carbonate (133 mg, 0.409 mmol) and Pd(dppf)Cl₂ (6mg, 0.00819 mmol), again degassed and purged with nitrogen for 15 minand the RM heated to 85° C. for 4 hr in a sealed tube. After completionof the reaction the RM was cooled to rt and diluted with chloroform andfiltered through celite bed. The organic layer was completely distilledoff to get the crude product, which was passed through 100-200 meshsilica gel eluting the pure compound at 5% ethyl aceate in hexane as offwhite colored solid compound 200.

Step 3:

To a stirred solution of 200 (60 mg, 0.112 mmol) in methanol (10 mL) wasadded water (5 mL) and potassium carbonate (46 mg, 0.336 mmol) and theRM heated to 60° C. overnight. After completion of the reaction, the RMwas completely distilled off and diluted with water and extract withchloroform twice. The organic layer was dried over sodium sulphate andcompletely distilled off to get the crude product, which was passedthrough 100-200 mesh silica gel eluting the pre compound at 28-30% ethylacetate in hexane as eluent to get the pale yellow colored solidcompound 201. ¹H NMR (CDCl3) δ: 9.30 (S, 1-H), 8.42 (d, J=353.77, 1-H),7.58 (m, J=8.29 2-H), 7.2 (d, J=8.29, 1-H), 7.13 (m, J=21.21, 3-H), 7.11(m, J=3.04, 1-H), 6.93 (m, J=4.74, 2-H) 3.79 (t, J=7.43, 4-H), 2.13 (m,J=7.56, 2-H) and MS m/z=396.3 (M+H)⁺.

Preparation of Example 973-(3-(pyrrolidin-1-ylsulfonyl)phenyl)-4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine(205)

Step 1:

To a stirred solution of 16 (150 mg, 0.347 mmol) and 202 (88 mg, 0.347mmol) in acetonitrile (5 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (226 mg, 0.694 mmol) and Pd(dppf)Cl₂ (14mg, 0.0176 mmol), again degassed and purged with nitrogen for 15 min andthe RM heated to 85° C. for 4 hr in a sealed tube. After completion ofthe reaction the RM was cooled to rt and diluted with chloroform andfiltered through celite bed the organic layer was completely distilledoff to get the crude product, which was passed through 100-200 meshsilica gel eluting the pure compound at 5% ethyl aceate in hexane as offwhite colored solid compound 203.

Step 2:

To a stirred solution of 203 (100 mg, 0.193 mmol) and 22 (24 mg, 0.193mmol) in acetonitrile (5 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (126 mg, 0.387 mmol) and Pd(dppf)Cl₂ (8mg, 0.00968 mmol), again degassed and purged with nitrogen for 15 minand the RM was eated to 85° C. for 4 hr in a sealed tube. Aftercompletion of the reaction the RM was cooled to rt and diluted withchloroform and filtered through celite bed. The organic layer wascompletely distilled off to get the crude product, which was passedthrough 100-200 mesh silica gel eluting the pure compound at 5% ethylaceate in hexane as off white colored solid compound 204.

Step 3:

To a stirred solution of 204 (60 mg, 0.106 mmol) in methanol (10 mL) wasadded water (5 mL) and potassium carbonate (44 mg, 0.319 mmol) and heatthe RM to 60° C. overnight. After completion of the SM, the RM wascompletely distilled off and diluted with water and extract withchloroform twice. The organic layer was dried over sodium sulphate andcompletely distilled off to get the crude product, which was passedthrough 100-200 mesh silica gel eluting the pre compound at 28-30% ethylacetate in hexane as eluent to get the pale yellow colored solidcompound 205. ^(1H) NMR (CDCl3) δ: 9.31 (1H), 8.40 (d, J=4.75 1H), 7.69(s, 1H), 7.60 (m, J=7.56 1H), 7.43 (d, J=2.56 1H), 7.17 (m, J=6.95 2H),7.07 (m, J=3.17 2H), 6.97 (m, J=2.19 1H), 6.84 (m, J=4.87 1H), 3.22 (m,J=6.70 4H), 1.77 (m, J=2.92 4H) and MS m/z=410.3 (M+H)⁺.

Preparation of Example 983-(4-(pyrrolidin-1-ylsulfonyl)phenyl)-4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine(209)

Step 1:

To a stirred solution of 16 (150 mg, 0.347 mmol) and 206 (88 mg, 0.347mmol) in acetonitrile (5 mL) was degassed and purged with nitrogen for10 min, was added cesium carbonate (226 mg, 0.694 mmol) and Pd(dppf)Cl₂(14 mg, 0.0173 mmol), again degassed and purged with nitrogen for 15 minand the RM heated to 85° C. for 4 hr in a sealed tube. After completionof the reaction the RM was cooled to rt and diluted with chloroform andfiltered through celite bed. The organic layer was completely distilledoff to get the crude product, which was passed through 100-200 meshsilica gel eluting the pure compound at 5% ethyl aceate in hexane as offwhite colored solid compound 207.

Step 2:

To a stirred solution of 207 (100 mg, 0.193 mmol) and 22 (24 mg, 0.193mmol) in acetonitrile (5 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (126 mg, 0.387 mmol) and Pd(dppf)Cl₂ (8mg, 0.00968 mmol), again degassed and purged with nitrogen for 15 minand the RM heated to 85° C. for 4 hr in a sealed tube. After completionof the reaction the RM was cooled to rt and diluted with chloroform andfiltered through celite bed. The organic layer was completely distilledoff to get the crude product, which was passed through 100-200 meshsilica gel eluting the pure compound at 5% ethyl aceate in hexane as offwhite colored solid compound 208.

Step 3:

To a stirred solution of 208 (50 mg, 0.0886 mmol) in methanol (10 mL)was added water (5 mL) and potassium carbonate (36.8 mg, 0.265 mmol) andthe RM heated to 60° C. overnight. After completion of the SM, the RMwas completely distilled off and diluted with water and extract withchloroform twice. The organic layer was dried over sodium sulphate andcompletely distilled off to get the crude product, which was passedthrough 100-200 mesh silica gel eluting the pre compound at 28-30% ethylacetate in hexane as eluent to get the pale yellow colored solidcompound 209. ¹H NMR (CDCl3) δ: 9.18 (s, 1H), 8.40 (d, J=5.00 1H), 7.56(m, J=8.29 2-H), 7.45 (d, J=43.93 1-H), 7.16 (m, J=6.46 3H), 7.08 (m,J=3.04 1-H), 6.91 (m, J=4.63 2-H), 3.25 (m J=6.70 4-H) 1.82 (m J=6.584-H) and MS m/z=409.9 (M+H)⁺.

Preparation of Example 994-(thiophen-3-yl)-3-(2-(trifluoromethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridine(213)

Step 1:

To a stirred solution of 16 (150 mg, 0.347 mmol) and 210 (48 mg, 0.347mmol) in acetonitrile (5 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (226 mg, 0.694 mmol) and Pd(dppf)Cl₂ (14mg, 0.0173 mmol), again degassed and purged with nitrogen for 15 min andthe RM heated to 85° C. for 4 hr in a sealed tube. After completion ofthe reaction the RM was cooled to rt and diluted with chloroform andfiltered through celite bed. The organic layer was completely distilledoff to get the crude product, which was passed through 100-200 meshsilica gel eluting the pure compound at 5% ethyl aceate in hexane as offwhite colored solid compound 211.

Step 2:

To a stirred solution of 211 (100 mg, 0.214 mmol) and 22 (27.3 mg, 0.214mmol) in acetonitrile (5 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (174 mg, 0.535 mmol) and Pd(dppf)Cl₂ (7mg, 0.0107 mmol), again degassed and purged with nitrogen for 15 min andthe RM heated to 85° C. for 4 hr in a sealed tube. After completion ofthe reaction the RM was cooled to rt and diluted with chloroform andfiltered through celite bed. The organic layer was completely distilledoff to get the crude product, which was passed through 100-200 meshsilica gel eluting the pure compound at 5% ethyl aceate in hexane as offwhite colored solid 212.

Step 3:

To a stirred solution of 212 (50 mg, 0.097 mmol) in methanol (10 mL) wasadded water (5 mL) and potassium carbonate (40 mg, 0.291 mmol) and theRM heated to 60° C. overnight. After completion of the sm the RM wascompletely distilled off and diluted with water and extract withchloroform twice. The organic layer was dried over sodium sulphate andcompletely distilled off to get the crude product, which was passedthrough 100-200 mesh silica gel eluting the pre compound at 28-30% ethylacetate in hexane as eluent to get the pale yellow colored solidcompound 213. ¹H NMR (CDCl3) δ: 9.52 (S, 1-H), 8.37 (d, J=5.00 1-H),7.44 (S, 1-H), 7.20 (m, J=8.29 1-H), 7.18 (m, J=3.78 2-H), 7.02 (mJ=5.00 3-H), 6.89 (m, J=2.92 1-H), 6.85 (m, J=4.87 1-H) and MS m/z=361.2(M+H)⁺.

Preparation of Example 1003-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine(217)

Step 1:

To a stirred solution of 16 (150 mg, 0.347 mmol) and 214 (77 mg, 0.347mmol) in acetonitrile (5 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (226 mg, 0.694 mmol) and Pd(dppf)Cl₂ (14mg, 0.0176 mmol), again degassed and purged with nitrogen for 15 min andthe RM was heated to 85° C. for 4 hr in a sealed tube. After completionof the reaction the RM was cooled to rt and diluted with chloroform andfiltered through celite bed. The organic layer was completely distilledoff to get the crude product, which was passed through 100-200 meshsilica gel eluting the pure compound at 5% ethyl aceate in hexane as offwhite colored solid compound 215.

Step 2:

To a stirred solution of 215 (100 mg, 0.206 mmol) and 22 (26.4 mg, 0.206mmol) in acetonitrile (5 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (134 mg, 0.412 mmol) and Pd(dppf)Cl₂(6.7 mg, 0.0082 mmol), again degassed and purged with nitrogen for 15min and the RM was heated to 85° C. for 4 hr in a sealed tube. Aftercompletion of the reaction the RM was cooled to rt and diluted withchloroform and filtered through celite bed. The organic layer wascompletely distilled off to get the crude the crude was passed through100-200 mesh silica gel eluting the pure compound at 5% ethyl aceate inhexane as off white colored solid compound 216.

Step 3:

To a stirred solution of 216 (60 mg, 0.112 mmol) in methanol (10 mL) wasadded water (5 mL) and potassium carbonate (46 mg, 0.336 mmol) and theRM heated to 60° C. overnight. After completion of the SM, the RM wascompletely distilled off and diluted with water and extract withchloroform twice. the organic layer was dried over sodium sulphate andcompletely distilled off to get the crude product, which was passedthrough 100-200 mesh silica gel eluting the pre compound at 28-30% ethylacetate in hexane as eluent to get the pale yellow colored solidcompound 217. ¹H NMR (CDCl3) δ: 9.53 (S, 1-H), 8.39 (d, J=4.87 1-H),7.44 (d, J=2.31 1-H), 7.40 (d, J=4.87 1-H), 7.06 (m, J=3.04 2-H), 6.97(m, J=7.19 1-H), 6.80 (m, J=9.63 3-H) and MS m/z=378.8 (M+H)⁺.

Preparation of Example 1013-(2,6-dimethoxypyridin-3-yl)-4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine(221)

Step 1:

To a stirred solution of 16 (150 mg, 0.347 mmol) and 218 (63.5 mg, 0.347mmol) in acetonitrile (5 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (226 mg, 0.694 mmol) and Pd(dppf)Cl₂ (14mg, 0.0173 mmol), again degassed and purged with nitrogen for 15 min andthe RM heated to 85° C. for 4 hr in a sealed tube. After completion ofthe reaction the RM was cooled to rt and diluted with chloroform andfiltered through celite bed the organic layer was completely distilledoff to get the crude product, which was passed through 100-200 meshsilica gel eluting the pure compound at 5% ethyl aceate in hexane as offwhite colored solid compound 219.

Step 2:

To a stirred solution of 219 (100 mg, 0.225 mmol) and 22 (29 mg, 0.225mmol) in acetonitrile (5 mL), degassed and purged with nitrogen for 10min, was added cesium carbonate (183 mg, 0.563 mmol) and Pd(dppf)Cl₂(7.3 mg, 0.00112 mmol), again degassed and purged with nitrogen for 15min and the RM heated to 85° C. for 4 hr in a sealed tube. Aftercompletion of the reaction the RM was cooled to rt and diluted withchloroform and filtered through celite bed. The organic layer wascompletely distilled off to get the crude product, which was passedthrough 100-200 mesh silica gel eluting the pure compound at 5% ethylaceate in hexane as off white colored solid compound 220.

Step 3:

To a stirred solution of 220 (50 mg, 0.101 mmol) in methanol (10 mL) wasadded water (5 mL) and potassium carbonate (42 mg, 0.305 mmol) and theRM heated to 60° C. overnight. After completion of the SM, the RM wascompletely distilled off and diluted with water and extract withchloroform twice. The organic layer was dried over sodium sulphate andcompletely distilled off to get the crude product, which was passedthrough 100-200 mesh silica gel eluting the pre compound at 28-30% ethylacetate in hexane as eluent to get the pale yellow colored solidcompound 221. ¹HNMR (400 MHz, CDCl₃) δ: 9.26 (S, 1-H), 8.34 (d, J=4.751-H), 7.33 (m, J=6.21 2-H), 7.10 (m, J=5.00 2-H), 6.91 (m, J=5.48 2-H),6.22 (d, J=7.92 1-H), 3.88 (S, 3-H), 3.47 (S, 3-H) and MS m/z=337.8(M+H)⁺.

Preparation of Example 1133-(2-methoxyphenyl)-5-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine (224)

Step 1:

A solution of 115 (0.150 g, 0.315 mmol) and 222 (0.048 g, 0.315 mmol) inacetonitrile (7 mL) in a sealed tube was added Cs₂CO₃ (0.204 gm, 0.628mmol) and degassed for 15 min. To the resulting RM was added Pd(dppf)Cl₂DCM (0.012 gm, 0.0157 mmol) and degassed again for another 15 min andthe contents were stirred for 3 hr at 90° C. After TLC monitoring, theRM allowed to cool to rt and diluted with DCM (50 mL) and filteredthrough celite and evaporated. The resulting crude material was purifiedthorough silica gel chromatography using a gradient of 6% ethyl acetate:hexane to afford the pure compound 223.

Step 2:

A solution of 223 (0.1 g, 0.219 mmol) and 22 (26 mg, 0.219 mmol) inacetonitrile (7 mL) in a sealed tube was added Cs₂CO₃ (143 mg, 0.438mmol) and degassed for 15 min. To the RM was Pd(PPh₃)₄ (12.6 mg, 0.0109mmol) and degassed again for 15 min. RM stirred for 3 hr at 90° C. Aftercompletion of the reaction, the RM was allowed to cool to rt and dilutedwith DCM (50 mL) and filtered through celite. The resulting crudematerial was purified through silica gel chromatography using a gradientof 6% ethyl acetate: hexane to afford the compound 224.

Step 3:

A solution of 224 (0.060 g, 0.1247 mmol) in MeOH (5 mL), water (5 mL)and K₂CO₃ (0.051 g, 0.3742 mmol) was stirred overnight at 70° C. Afterthe termination of reaction was allowed to cool and the solvents wereremoved and diluted with DCM (50 mL), extracted and the organic layerwashed with water and dried over Na₂SO₄ and evaporated. The resultingcrude material was purified through silica gel chromatography using agradient of 25% ethyl acetate: hexane to afford title compound 225.¹HNMR (400 MHz, CDCl₃) δ: 8.87 (s, 1H), 8.59 (d, 1H), 8.24 (d, 1H), 7.60(m, 2H), 7.43 (m, 3H), 7.31 (m, 1H), 7.07 (m, 2H), 3.88 (s, 3H), MSm/z=306.8 (M+H)⁺.

Preparation of Example 1143-(2-chloro-3-fluorophenyl)-5-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine(229)

Step 1:

A solution of 115 (0.150 g, 0.315 mmol) and 226 (0.54.8 mg, 0.315 mmol)in acetonitrile (7 mL) in a sealed tube was added Cs₂CO₃ (0.206 g, 0.628mmol) and degassed for 15 min. To the resulting RM was added Pd(dppf)Cl₂DCM (0.012 g, 0.0157 mmol) and degassed again for another 15 min and thecontents were stirred for 3 hr at 90° C. After TLC monitoring, the RMallowed to cool to rt and diluted with DCM (50 mL) and filtered throughcelite and evaporated. The resulting crude material was purifiedthorough silica gel chromatography using a gradient of 6% ethyl acetate:hexane to afford the pure compound 227.

Step 2:

A solution of 227 (0.1 g, 0.219 mmol) and 22 (26.7 mg, 0.209 mmol) inacetonitrile (7 mL) in a sealed tube was added Cs₂CO₃ (137 mg, 0.418mmol) and degassed for 15 min. To the RM was Pd(PPh₃)₄ (12 mg, 0.0104mmol) and degassed again for 1 min. RM stirred for 3 hr at 90° C. Aftercompletion of the reaction was allowed to cool to rt and diluted withDCM (50 mL) and filtered through celite. The resulting crude materialwas purified trhough silica gel chromatography using a gradient of 6%ethyl acetate: hexane to afford the compound 228.

Step 3:

A solution of 228 (0.060 g, 0.1247 mmol) in MeOH (5 mL), water (5 mL)and K₂CO₃ (0.051 g, 0.3742 mmol) was stirred overnight at 70° C. Afterthe termination of reaction was allowed to cool and the solvents wereremoved and diluted with DCM (50 mL) extracted and the organic layerwashed with water and dried over Na₂SO₄ and evaporated. The resultingcrude material was purified through silica gel chromatography using agradient of 25% ethyl acetate: hexane to afford title compound 229.¹HNMR (400 MHz, CDCl₃) δ: ¹HNMR (400 MHz, CDCl₃): 9.41 (s, 1H), 8.65 (s,1H), 8.11 (s, 1H), 7.60 (d, 1H), 7.44 (m, 3H), 7.34 (m, 2H), 7.18 (m,1H), MS m/z=328.8 (M+H)⁺.

Preparation of Example 1153-(2-methoxyphenyl)-5-(5-methylfuran-2-yl)-1H-pyrrolo[2,3-b]pyridine(119)

Step 1:

A solution of 115 (150 mg, 0.314 mmol) and 116 (47 mg, 0.314 mmol) inacetonitrile (7 mL) was taken into a sealed tube, Cs₂CO₃ (204 mg, 0.628mmol) added, and degassed for 15 min. To the RM was added Pd(dppf)Cl₂DCM (0.012 g, 0.01572 mmol) and degassed again for 15 min, and stirredfor 4 hr at 90° C. After 2 hr, the TLC confirmed the reaction and the RMallowed to cool to rt. The crude material was taken in to DCM (100 mL)and filtered through celite. The resulting crude material was purifiedvia silica gel chromatography using a gradient of 5% ethyl acetate:hexane to afford compound 117.

Step 2:

A solution of 117 (0.075 g, 0.164 mmol.) and 118 (0.034 g, 0.1641 mmol)in 5 mL acetonitrile in a sealed tube was added Cs₂CO₃ (0.04 g, 0.628mmol), and degassed for 15 min in presence of Pd(PPh₃)₄. The resultingRM was stirred overnight at 90° C., allowed to cool to rt and taken into DCM (100 mL) and filtered through celite. The resulting oil waspurified via silica gel chromatography using a gradient of 10% ethylacetate: hexane to afford compound 119.

Step 3:

To a solution of 119 (0.070 g, 0.1528 mmol) in MeOH (5 mL) and H₂O (5mL) was added K₂CO₃ and the RM stirred overnight at 70° C. The resultingRM was allowed to cool and evaporated completely and extracted in to DCM(50 mL) followed by water wash for two times. Organic layer was driedwith Na₂SO₄ and evaporated. The crude product was purified by silica gelchromatography using a gradient of 25% ethyl acetate: hexane to affordcompound 120. ¹H NMR (400 MHz, CDCl₃) δ:8.95 (s, 1H), 8.64 (s, 1H), 8.28(d, 1H), 7.61 (m, 2H), 7.33 (m, 1H), 7.12 (m, 2H), 6.53 (d, 1H), 6.06(d, 1H), 3.88 (s, 3H), 2.38 (s, 3H). MS m/z 304.91 [M+1-1]⁺.

Preparation of Example 1182-(4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenol (161)

Compound 161:

¹HNMR (400 MHz, CDCl₃) δ: 9.41 (bs, 1H), 8.26 (bs, 1H), 7.67 (m, 2H),7.52 (m, 4H), 7.32 (m, 2H), 7.01 (m, 1H), 6.96 (m, 2H), MS m/z ESI:278.8 (M+H)⁺.

Preparation of Example 1203-(3-fluoro-2-methoxyphenyl)-4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine(145)

Compound 145:

¹HNMR (400 MHz, CDCl₃) δ: 9.43 (1s, 1H) 8.37 (d, 1H), 8.36 (m, 1H), 7.15(d, 1H), 7.14 (m, 1H), 6.94 (m, 3H), 6.93 (m, 2H), 3.53 (s, 3H), MS m/z:324.0 (M+H)⁺.

Preparation of Example 1213-(3,5-difluoro-2-methoxyphenyl)-4-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine(149)

Compound 149:

¹HNMR (400 MHz, CDCl₃) δ: 9.8 (b, 1H), 8.39 (d, 1H), 7.48 (s, 1H) 7.15(m, 2H) 7.0 (m, 1H), 6.7 (m, 1H), 6.7 (m, 1H), 6.43 (m, 1H), 3.52 (m,3H), MS m/z ESI: +342.9 (M+H)⁺.

Preparation of Example 1222-fluoro-6-(5-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenol (128)

Step 1:

A solution of 115 (150 mg, 0.314 mmol.) and 121 (49 mg, 0.3144 mmol) wasdissolved in acetonitrile (10 mL) in a sealed tube and was charged withCs₂CO₃ (204 mg, 0.628 mmol). The resulting RM was degassed for 15 min.To this RM was added Pd(dppf)Cl₂ DCM (12 mg, 0.0157 mmol) and degassedagain for 15 min. RM was stirred for 4 hr at 90° C. After 4 hr and TLCmonitoring confirms the consumption of SM, the RM was cooled to rt anddiluted with DCM (100 mL) and filtered through celite. The resultingcrude material was purified through silica gel chromatography using agradient of 5% ethyl acetate in hexane afforded the compound 122.

Step 2:

A solution of 122 (125 mg, 0.271 mmol) and 22 (34 mg, 0.27 mmol) wasdissolved in acetonitrile (5 mL) in a sealed tube. To this RM was addedCs₂CO₃ (176 mg, 0.542 mmol) and subjected to degassing for 15 min. Thecatalyst Pd(PPh₃)₄ (15 mg, 0.0135 mmol) was added and degassed again for15 min. The resulting RM was stirred overnight at 90° C. After TLC withthe Rf changes from the SM confirmed the completion of the reaction, thecontents were cooled to rt and diluted with DCM (100 mL) and filteredthrough celite. The resulting crude material was purified from silicagel chromatography using a gradient of 10% ethyl acetate: hexane toafford compound 123.

Step 3:

Compound 123 (50 mg, 0.105 mmol) in MeOH (10 mL) and H₂O (5 mL) wasadded K₂CO₃ (36 mg, 0.262 mmol) and the RM was stirred overnight at 70°C. After completion of the reaction from TLC, the solvent MeOH wasevaporated completely and the crude material was diluted with DCM (50mL) followed by water wash for two times and the organic layer was driedwith Na₂SO₄ and evaporated. The resulting crude compound was purifiedfrom silica gel chromatography using a gradient of 25% ethyl acetate:hexane to afford the compound 128. 1HNMR (400 MHz, CDCl3) □: 10.24 (s,1H), 8.55 (s, 1H), 8.33 (d, 1H), 7.67 (s, 1H), 7.43 (m, 3H), 7.1 (d,1H), 7.09 (m, 1H), 6.96 (m, 1H), 5.34 (s, 1H), MS m/z: 310.8 (M+H)+.

Preparation of Example 1232-(5-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenol (132)

Step 1:

A solution of 115 (150 mg, 0.314 mmol.) and 129 (43 mg, 0.314 mmol) wasdissolved in acetonitrile (10 mL) in a sealed tube and charged withCs₂CO₃ (204 mg, 0.628 mmol). The resulting RM was degassed for 15 min.To this RM was added Pd(dppf)Cl₂ DCM (12 mg, 0.0157 mmol) and degassedagain for 15 min. RM was stirred for 4 hr at 90° C. After 4 hr and TLCmonitoring confirmed the consumption of SM, the contents of reaction wascooled to rt and diluted with DCM (100 mL) and filtered through celite.The resulting crude material was purified through silica gelchromatography using a gradient of 5% ethyl acetate in hexane to affordthe compound 130.

Step 2:

A solution of 130 (100 mg, 0.25 mmol) and 22 (34 mg, 0.27 mmol) wasdissolved in acetonitrile (5 mL) in a sealed tube. To this RM was addedCs₂CO₃ (147 mg, 0.542 mmol) and degassed for 15 min. The catalystPd(PPh₃)₄ (13 mg, 0.0122 mmol) was added and degassed again for 15 min.The resulting RM was stirred overnight at 90° C. After TLC with the Rfchanges from the SM confirmed the completion of the reaction, thecontents were cooled to rt and diluted with DCM (100 mL) and filteredthrough celite. The resulting crude material was purified from silicagel chromatography using a gradient of 10% ethyl acetate: hexane toafford compound 131.

Step 3:

Compound 131 (60 mg, 0.131 mmol) in MeOH (10 mL) and H₂O (5 mL) wasadded K₂CO₃ (45 mg, 0.38 mmol) and the RM was stirred overnight at 70°C. After completion of the reaction from TLC, the solvent MeOH wasevaporated completely and the crude material was diluted with DCM (50mL) followed by water wash for two times and the organic layer was driedwith Na₂SO₄ and evaporated. The resulting crude compound was purifiedfrom silica gel chromatography using a gradient of 25% ethyl acetate:hexane to afford the compound 132. ¹HNMR (400 MHz, CDCl₃) δ: 11.80 (s,1H), 9.53 (s, 1H), 8.62 (d, 1H), 8.30 (d, 1H), 7.87 (m, 1H), 7.74 (d,2H), 7.6 (m, 3H), 7.13 (m, 1H), 6.93 (m, 2H). MS m/z: 292.7 (M+H)⁺.

Preparation of Example 1242,4-difluoro-6-(5-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenol(153)

Compound 153:

¹HNMR (400 MHz, CDCl₃) δ: 12.0 (s, 1H), 8.64 (d, 1H), 8.31 (d, 1H), 7.90(m, 1H), 7.84 (s, 1H), 7.65 (m, 2H), 7.22 (m, 1H), 7.1 (m, 1H), MS m/zESI: 328.8. (M+H)⁺.

Preparation of Example 1253-(3-fluoro-2-methoxyphenyl)-5-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine(124)

Step 1:

To a solution of 115 (0.150 g, 0.314 mmol.) and 121 (0.049 g, 0.314mmol) in a sealed tube was dissolved acetonitrile (7 mL) and then Cs₂CO₃(0.204 g, 0.628 mmol) was charged. The resulting RM was degassed for 15min. To this RM was added Pd(dppf)Cl₂ DCM (0.012 g, 0.0157 mmol) anddegassed again for 15 min. The resulting RM was stirred for 2 hr at 90°C. After 4 hr, TLC monitoring confirmed the consumption of SMs and theRM was cooled to rt and diluted with DCM (100 mL) and filtered throughcelite. The resulting crude material was purified via silica gelchromatography using a gradient of 5% ethyl acetate in hexane to affordcompound 122.

Step 2:

A solution of 122 (0.100 g, 0.210 mmol) and 22 (0.027 g, 0.210 mmol) wasdissolved in acetonitrile (5 mL) in a sealed tube. To this RM, Cs₂CO₃(0.137 g, 0.421 mmol) was added and degassed for 15 min. The catalystPd(PPh₃)₄ (0.012 g, 0.010 mmol) was added and degassed again for 15 min.The resulting RM was stirred overnight at 90° C. After TLC showedcompletion of changes from the SM, the RM was allowed to cool to rt. DCM(100 mL) was added and filtered through celite. The resulting oil waspurified via silica gel chromatography at a gradient of 10% ethylacetate: hexane to afford compound 123.

Step 3:

To Compound 123 (0.050 g, 0.104 mmol) in MeOH (10 mL) and H₂O (5 mL) wasadded K₂CO₃ (0.035 g, 0.260 mmol) and the RM stirred overnight at 70° C.After completion of the reaction from TLC, the resulting contents wereevaporated of methanol completely and diluted with DCM (50 mL) followedby water wash for two times and the organic layer was dried with Na₂SO₄and evaporated. The resulting crude was purified via silica gelchromatography using a gradient of 25% ethyl acetate: hexane to affordcompound 124.

¹HNMR (400 MHz, CDCl3): 9.26 (s, 1H), 8.63 (s, 1H), 8.31 (d, 1H), 7.69(d, 1H), 7.48 (d, 1H), 7.44 d, 2H), 7.38 (m, 1H), 7.11 (m, 2H), 3.75 (s,3H). MS m/z: 324.8 (M+H)+.

Preparation of Example 1263-(3,5-difluoro-2-methoxyphenyl)-5-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine(157)

Compound 157:

¹HNMR (400 MHz, CDCl₃) δ: 12.14, (t, 1H), 6.8 (m, 1H), 8.32 (m, 1H),7.87 (m, 2H), 7.65 (m, 2H), 7.31 (m, 2H), 3.61 (m, 3H), MS m/z ESI:342.8 (M+H)⁺.

Preparation of Example 1282-fluoro-6-(5-(5-methylfuran-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenol(136)

Compound 136:

¹HNMR (400 MHz, CDCl₃) δ: 10.03 (s, 1H), 8.61 (d, 1H), 8.31 (d, 1H),7.65 (s, 1H), 7.34 (m, 1H), 7.12 (m, 1H), 6.99 (m, 1H), 6.54 (d, 1H),6.07 (d, 1H), 2.13 (s, 3H), MS m/z: 308.8 (M+H)⁺.

Preparation of Example 1293-(2-chloro-3-fluorophenyl)-5-(5-methylfuran-2-yl)-1H-pyrrolo[2,3-b]pyridine(163)

Compound 163:

¹HNMR (400 MHz, CDCl₃) δ: 9.99 (S, 1H), 8.16 (d, 1H), 7.62 (d, 1H), 7.36(m, 2H), 7.19 (m, 1H), 7.56 (d, 1H), 6.08 (m, 1H), MS m/z ESI: 326.9(M+H)⁺.

Preparation of Example 1313-(2-chloro-3-fluorophenyl)-5-(4-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridine(141)

Compound 141:

¹HNMR (400 MHz, CDCl₃) δ: 9.08 (s, 1H), 8.62 (s, 1H), 8.09 (s, 1H), 7.59(d, 1H), 7.34 (m, 2H), 7.32 (m, 1H), 7.12 (s, 1H), 6.88 (t, 1H) 2.30 (s,3H), MS m/z: 342.7 (M+H)⁺.

Preparation of Example 1334-((5-((3-(2-chloro-3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiophen-2-yl)methyl)morpholine(263)

Step 1:

To a solution of 227 (100 mg, 0.208 mmol) and 236 (47 mg, 0.208 mmol),in acetonitrile (7 mL) was added cesium carbonate (135 mg, 0.416 mmol).The RM was degassed and purged with nitrogen for 10 min. Pd(dppf)Cl₂ (8mg, 0.01042 mmol) was added to the reaction. The RM was again degassedand purged with nitrogen for another 5 min, and heated to 80° C. in asealed tube overnight. The reaction was allowed to cool to rt anddiluted with chloroform. The organic layer was concentrated to get thecrude product, which was purified through flash chromatography by using100-200 mesh silica gel. The compound was eluted at 40% ethyl acetate inhexane as half white colored solid compound 262.

Step 2:

A solution of 262 (60 mg, 0.103 mmol) in methanol (20 mL) and water (5mL) was added potassium carbonate (42 mg, 0.3092 mmol). The reaction washeated to 60° C. overnight. The solvent was completely distilled off andthe remainder diluted with water (25 mL) and extracted with chloroformtwice (2×25 mL). The combined organic layer was dried over sodiumsulphate, filtered and concentrated to get the crude material, which waspurified through flash chromatography by using 100-200 mesh silica gel.The compound was eluted at 60% ethyl acetate in hexane as pale yellowsolid compound 263. ¹HNMR (400 MHz, CDCl3): 9.42 (bs, 1H), 8.62 (d, 1H),8.07 (d, 1H), 7.60 (d, 1H), 7.32 (m, 2H), 7.17 (m, 2H), 6.90 (d, 1H),4.05 (m, 4H), 3.74 (m, 6H), 3.44 (m, 4H), MS-ES+ 426.01.

Preparation of Example 1353-(3-(2-chloro-3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N,N-dimethylbenzenesulfonamide(231)

Compound 232:

¹H NMR (400 MHz, CDCl₃) δ: 9.86 (s, 1H), 8.63 (d, 1H), 8.13 (d, 1H),8.01 (s, 1H), 7.85 (d, 1H), 7.77 (m, 1H), 7.65 (m, 2H), 7.35 (m, 2H),7.19 (m, 1H), 2.76 (s, 6H), MS m/z=329.9 (M+H)⁺.

Preparation of Example 1383-(3-chloro-2-fluorophenyl)-5-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine(165)

Compound 165

¹HNMR (400 MHz, CDCl₃) δ: 9.71 (m, 1H), 8.66 (d, 1H), 8.27 (s, 1H), 7.67(s, 1H), 7.58 (m, 1H), 7.5 (m, 1H), 7.49 (m, 2H), 7.45 (m, 1H), 7.19 (t,1H), MS m/z ESI: 328.8 (M+H)⁺.

Preparation of Example 1393-(2-chlorophenyl)-5-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine (169)

Compound 169:

¹HNMR (400 MHz, CDCl₃) δ: 9.7 (S, 1H), 8.65 (d, 1H), 8.13 (d, 1H), 7.6(d, 1H), 7.54 (m, 2H), 7.46 (m, 1H), 7.43 (m, 2H), 7.42 (m, 2H), MS m/zESI: 310.8 (M+H)⁺.

Preparation of Example 1403-(3-chloro-4-fluorophenyl)-5-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine(173)

Compound 173:

¹HNMR (400 MHz, CDCl₃) δ: 9.09 (b, 1H), 8.64 (m, 1H), 8.28 (S, 1H), 7.66(d, 1H), 7.46-749 (m, 4H), MS m/z ESI: 326.8, (M+H)⁺.

Preparation of Example 1424-((5-(3-(3-fluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiophen-2-yl)methyl)morpholine(235)

Compound 235:

¹HNMR (400 MHz, CDCl₃) δ: 8.94 (s, 1H), 8.61 (d, 1H), 8.26 (d, 1H), 7.66(d, 1H), 7.35 (m, 1H), 7.15 (m, 1H), 7.06 (m, 3H), 6.90 (d, 1H), 3.76(m, 3H), 3.72 (s, 2H), 2.54 (m, 4H), 1.94 (m, 4H), MS m/z=422.1 (M+H)⁺.

Preparation of Example 1434-((5-(3-(3,5-difluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiophen-2-yl)methyl)morpholine(238)

Compound 238:

¹HNMR (400 MHz, CDCl₃) δ: 9.26 (bs, 1H), 8.63 (bs, 1H), 8.27 (s, 1H),7.71 (d, 1H), 7.17 (d, 1H), 7.09 (m, 1H), 6.92 (d, 1H), 6.84 (m,), 3.75(m, 5H), 2.55 (bs, 4H), 1.95 (m, 2H), 1.68 (m, 2H), MS m/z=440.1 (M+H)⁺.

Preparation of Example 1485-(5-chlorothiophen-2-yl)-3-(3-fluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine(254)

Compound 254:

¹HNMR (400 MHz, CDCl₃) δ: 9.02 (s, 1H), 8.54 (s, 1H), 8.20 (d, 1H), 7.67(d, 1H), 7.33 (m, 1H), 7.09 (m, 3H), 6.92 (d, 1H), 3.76 (s, 3H); MSm/z=358.9 (M+H).

Preparation of Example 1675-(5-chlorothiophen-2-yl)-3-(3,5-difluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine(256)

Compound 256:

¹HNMR (400 MHz, CDCl₃) δ: 9.40 (s, H), 8.55 (d, 1H), 8.21 (d, 1H), 7.73(s, 1H), 7.09 (m, 2H), 6.93 (d, 1H), 6.85 (m, 1H), 3.69 (s, 3H), MSm/z=376.9 (M+H).

Preparation of Example 1683-(3-fluoro-2-methoxyphenyl)-5-(5-methylfuran-2-yl)-1H-pyrrolo[2,3-b]pyridine(259)

Compound 259:

¹HNMR (400 MHz, CDCl₃) δ: 9.91 (s, 1H), 8.68 (d, 1H), 8.34 (d, 1H), 7.69(s, 1H), 7.38 (d, 1H), 7.16 (m, 2H), 6.56 (d, 1H), 6.08 (d, 1H), 3.75(s, 1H), 2.40 (s, 3H), MS m/z=322.9 (M+H).

Preparation of Example 1693-(3,5-difluoro-2-methoxyphenyl)-5-(5-methylfuran-2-yl)-1H-pyrrolo[2,3-b]pyridine(261)

Compound 261:

¹HNMR (400 MHz, CDCl₃) δ: 9.32 (s, 1H), 8.67 (d, 1H), 8.32 (d, 1H), 7.71(s, 1H), 7.14 (m, 1H), 6.84 (m, 1H), 6.57 (m, 1H), 6.08 (m, 1H), 3.69(s, 3H), 2.41 (s, 3H), MS m/z=339.0 (M+H).

Preparation of Example 1743-(3-fluoro-2-methoxyphenyl)-5-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridine(266)

Compound 266:

¹HNMR (400 MHz, CDCl₃) δ: 9.19 (bs, 1H), 8.62 (s, 1H), 8.28 (bs, 1H),7.68 (d, 1H), 7.35 (d, 1H), 7.14 (m, 3H), 7.05 (s, 1H), 3.86 (s, 2H),3.76 (s, 3H), 2.64 (bs, 4H), 1.84 (bs, 4H), MS-ES+ 406.1 (M+H).

Preparation of Example 1753-(3-fluoro-2-methoxyphenyl)-5-(5-(piperidin-1-ylmethyl)thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridine(268)

Compound 268:

¹HNMR (400 MHz, CDCl₃) δ: 9.10 (bs 1H), 8.62 (d, 1H), 8.27 (d, 1H), 7.67(d, 1H), 7.36 (m, 1H), 7.12 (m, 3H), 6.89 (bs, 1H), 3.76 (m, 3H), 3.71(m, 2H), 2.48 (m, 4H), 1.62 (m, 4H), 1.45 (m, 2H), MS-ES+ 422.1 (M+H).

Preparation of Example 1764-(5-(3-(3-fluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazol-2-yl)morpholine(271)

Compound 271:

¹HNMR (400 MHz, CDCl₃) δ: 9.64 (s, 1H), 8.49 (s, 1H), 8.12 (d, 1H), 7.68(d, 1H), 7.33 (d, 1H), 7.14 (m, 1H), 7.08 (m, 2H), 3.85 (m, 4H), 3.75(s, 3H), 3.52 (m, 4H), MS-ES+ 411.0 (M+H).

Preparation of Example 1773-(3,5-difluoro-2-methoxyphenyl)-5-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridine(273)

Compound 273:

¹HNMR (400 MHz, CDCl₃) δ: 9.62 (s, 1H), 8.63 (d, 1H), 8.28 (d, 1H), 7.73(d, 1H), 7.17 (d, 1H), 7.09 (m, 1H), 6.92 (d, 1H), 6.84 (m, 1H), 3.86(s, 2H), 3.70 (s, 3H), 2.63 (bs, 4H), 1.83 (bs, 4H), MS-ES+ 426.0 (M+H).

Preparation of Example 1783-(3,5-difluoro-2-methoxyphenyl)-5-(5-(piperidin-1-ylmethyl)thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridine(275)

Compound 275:

¹HNMR (400 MHz, CDCl₃) δ: 9.49 (bs, 1H), 8.63 (s, 1H), 8.27 (d, 1H),7.73 (bs, 1H), 7.17 (d, 1H), 7.10 (m, 1H), 6.84 (m, 1H), 6.81 (m, 1H),4.05 (m, 2H), 3.70 (m, 5H), 3.48 (m, 2H), 2.48 (bs, 4H), 1.92 (m, 2H),MS-ES+ 440.0 (M+H).

Preparation of Example 1794-(5-(3-(3,5-difluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazol-2-yl)morpholine(277)

Compound 277:

¹HNMR (400 MHz, CDCl₃) δ: 9.43 (s, 1H), 8.51 (d, 1H), 8.12 (d, 1H), 7.72(d, 1H), 7.42 (s, 1H), 7.08 (m, 1H), 6.84 (m, 1H), 3.84 (m, 4H), 3.69(s, 3H), 3.53 (m, 4H), MS-ES+ 429.0 (M+H).

Preparation of Example 180N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-4-(thiophen-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine(240)

Compound 240:

¹HNMR (400 MHz, CDCl₃) δ: 8.61 (s, 1H), 8.32 (s, 1H), 8.09 (s, 1H), 7.80(m, 3H), 7.60 (m, 1H), 7.36 (d, 1H), 7.15 (m, 2H), 3.77 (s, 3H), 3.01(s, 3H), 1.39 (s, 9H): MS m/z=468.1 (M+H).

Preparation of Example 181N-(tert-butyl)-3-(3-(3,5-difluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methylbenzenesulfonamide(242)

Compound 242:

¹HNMR (400 MHz, CDCl₃) δ: 9.55 (s, 1H), 8.62 (s, 1H), 8.31 (s, 1H), 8.08(s, 1H), 7.79 (m, 3H), 7.60 (t, 1H), 7.10 (m, 1H), 6.85 (m, 1H), 3.70(s, 3H), 3.02 (s, 3H), 1.39 (s, 9H), MS m/z=486.1 (M+H).

Preparation of Example 1823-(3-fluoro-2-methoxyphenyl)-5-(3-(pyrrolidin-1-ylsulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine(245)

Compound 245:

¹HNMR (400 MHz, CDCl₃) δ: 9.25 (s, 1H), 8.61 (s, 1H), 8.31 (d, 1H), 8.08(d, 1H), 7.82 (m, 2H), 7.72 (d, 1H), 7.63 (t, 1H), 7.36 (m, 1H), 7.11(m, 2H), 3.76 (s, 3H), 3.30 (m, 4H), 1.79 (m, 4H), MS m/z=452.0 (M+H).

Preparation of Example 1833-(3,5-difluoro-2-methoxyphenyl)-5-(3-(pyrrolidin-1-ylsulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine(247)

Compound 247:

¹HNMR (400 MHz, CDCl₃) δ: 9.63 (s, 1H), 8.63 (s, 1H), 8.31 (s, 1H), 8.09(s, 1H), 7.85 (m, 2H), 7.67 (m, 1H), 7.63 (m, 1H), 7.09 (m, 1H), 6.86(m, 1H), 3.70 (s, 3H), 3.31 (m, 4H), 1.80 (m, 4H), MS m/z=470.1 (M+H).

Preparation of Example 1843-(3-(3-fluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N,N-dimethylbenzenesulfonamide(249)

Compound 249:

¹HNMR (400 MHz, CDCl₃) δ: 9.63 (s, 1H), 8.63 (s, 1H), 8.31 (s, 1H), 8.09(s, 1H), 7.85 (m, 2H), 7.67 (m, 1H), 7.63 (m, 1H), 7.09 (m, 1H), 6.86(m, 1H), 3.70 (s, 3H), 3.31 (m, 4H), 1.80 (m, 4H), MS m/z=470.1 (M+H).

Preparation of Example 1853-(3-(3,5-difluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N,N-dimethylbenzenesulfonamide(251)

Compound 251:

¹HNMR (400 MHz, CDCl₃) δ: 9.77 (s, 1H), 8.61 (s, 1H), 8.31 (s, 1H), 8.03(s, 1H), 7.86 (d, 1H), 7.78 (m, 2H), 7.65 (m, 1H), 7.09 (m, 1H), 6.86(m, 1H), 3.70 (s, 3H), 2.77 (s, 6H), MS m/z=446.13 (M+H).

Preparation of Example 1903-(3-fluoro-2-methoxyphenyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine(280)

Compound 280:

¹HNMR (400 MHz, CDCl₃) δ: 9.36 (s, 1H), 8.50 (s, 1H), 8.17 (d, 1H), 7.76(m, 2H), 7.65 (s, 1H), 7.35 (s, 1H), 7.08 (m, 2H), 4.29 (m, 1H), 4.05(m, 4H), 3.73 (s, 3H), 3.28 (m, 2H), 2.81 (m, 2H), MS-ES+ 392.1 (M+H).

Preparation of Example 1913-(3,5-difluoro-2-methoxyphenyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine(282)

Compound 282:

¹HNMR (400 MHz, CDCl₃) δ: 12.06 (s, 1H), 8.65 (s, 1H), 8.57 (s, 1H),8.40 (d, 1H), 8.30 (d, 1H), 8.20 (s, 1H), 7.82 (d, 1H), 7.25 (m, 2H),4.50 (m, 1H), 3.60 (s, 3H), 3.09 (m, 2H), 2.23 (m, 4H), MS-ES+ 410.1(M+H).

Preparation of Example 1922-(5-(5-(morpholinomethyl)thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenol(286)

Step 1:

To a solution of 115 (150 mg, 0.314 mmol) and (2-hydroxyphenyl)boronicacid 283 (43 mg, 0.314 mmol) in acetonitrile (5 mL) was added cesiumcarbonate (204 mg, 0.628 mmol). The resulting reaction was degassed andpurged with nitrogen for 10 min. Pd (dppf) Cl2 (12 mg, 0.0157 mmol) wasadded to the reaction and the reaction was again degassed and purgedwith nitrogen for another 5 min. The reaction was heated to 80° C. in asealed tube overnight. After completion, the reaction was allowed tocool to rt and diluted with chloroform. The organic layer wasconcentrated to get the crude, which was purified through flashchromatography by using 100-200 mesh silica gel. The compound was elutedat 30% ethyl acetate in hexane as half white coloured solid compound2-(5-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)phenol 284.

Step 2:

To a solution of compound 284 (100 mg, 0.225 mmol) and 236 (51 mg, 0.225mmol) in acetonitrile (5 mL) was added cesium carbonate (146 mg, 0.4451mmol). The reaction was degassed and purged with nitrogen for 10 min. Pd(dppf) Cl₂ (9 mg, 0.01127 mmol) was added to the reaction, which wasagain degassed and purged with nitrogen for another 5 min. The reactionwas heated to 80° C. in a sealed tube overnight. The reaction wasallowed to cool to rt and diluted with chloroform. The organic layer wasconcentrated to get the crude, which was purified through flashchromatography by using 100-200 mesh silica gel. The compound was elutedat 60% ethyl acetate in hexane as half-white coloured solid compound285.

Step 3:

To a solution of 285 (50 mg, 0.0916 mmol) in methanol (20 mL) and water(5 mL) was added potassium carbonate (37 mg, 0.274 mmol). The reactionwas heated to 60° C. overnight. The solvent was completely distilled offand the remainder diluted with water (25 mL) and extracted withchloroform twice (2×25 mL). The combined organic layer was dried oversodium sulphate, filtered, and concentrated to get the crude, which waspurified through flash chromatography by using neutral alumina. Thecompound was eluted at 0.5% methanol in dichloromethane as pale yellowsolid compound2-(5-(5-(morpholinomethyl)thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenol286. ¹H NMR (CDCl₃) δ: 9.33 (bs, 1H), 8.63 (bs, 1H), 8.11 (d, 1H), 7.52(d, 1H), 7.41 (m, 2H), 7.30 (m, 1H), 7.12 (m, 1H), 7.07 (m, 2H), 6.90(d, 1H), 3.76 (m, 6H), 2.53 (m, 4H) and MS m/z=392 (M+H).

Preparation of Example 1932-fluoro-6-(5-(5-(morpholinomethyl)thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenol(290)

Step 1:

To a solution of 288 (100 mg, 0.216 mmol) and 236 (49 mg, 0.216 mmol) inacetonitrile (7 mL) was added cesium carbonate (141 mg, 0.433 mmol). Thereaction was degassed and purged with nitrogen for 10 min. Pd(dppf)Cl₂.(8 mg, 0.108 mmol) was added to the RM, which was again degassed andpurged with nitrogen for another 5 min. The RM was heated to 80° C. in asealed tube overnight. The reaction was allowed to cool to rt anddiluted with chloroform. The organic layer was concentrated to get thecrude product, which was purified through flash chromatography by using100-200 mesh silica gel. The compound was eluted at 42% ethyl acetate inhexane as half white colored solid compound 289.

Step 2:

To a solution of 289 (50 mg, 0.0887 mmol) in methanol (15 mL) and water(5 mL) was added potassium carbonate (36 mg, 0.266 mmol). The RM washeated to 60° C. overnight. The solvent was completely distilled and theRM diluted with water (25 mL) and extracted with chloroform twice (2×25mL). The combined organic layer was dried over sodium sulphate, filteredand concentrated to get the crude compound, which was purified throughflash chromatography by using 100-200 mesh silica gel. The compound waseluted at 65% ethyl acetate in hexane as pale yellow solid compound 290.¹HNMR (400 MHz, CDCl3): 12.00 (bs, 1H), 9.62 (bs, 1H), 8.55 (d, 1H),8.17 (d, 1H), 7.77 (d, 1H), 7.35 (m, 2H), 7.12 (m, 1H), 6.97 (d, 1H),6.89 (m, 1H), 3.67 (bs, 2H), 3.57 (m, 4H), 2.43 (m, 4H); MS-ES+ 408.8

Preparation of Example 1944-((5-(3-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiophen-2-yl)methyl)morpholine(294)

Step 1:

To a solution of 115 (150 mg, 0.314 mmol) and 291 (63 mg, 0.314 mmol) inacetonitrile (5 mL) was added cesium carbonate (204 mg, 0.628 mmol). TheRM was degassed and purged with nitrogen for 10 min. Pd(dppf)Cl₂ (12 mg,0.0157 mmol) was added and the RM was again degassed and purged withnitrogen for another 5 min. The RM was heated to 80° C. in a sealed tubeovernight and then allowed to cool to rt and diluted with chloroform.The organic layer was concentrated to get the crude product, which waspurified through flash chromatography by using 100-200 mesh silica gel.The compound was eluted at 6% ethyl acetate in hexane as half whitecolored solid compound 292.

Step 2:

To a solution of 292 (100 mg, 0.197 mmol) and 236 (44 mg, 0.197 mmol) inacetonitrile (7 mL) was added cesium carbonate (128 mg, 0.394 mmol). TheRM was degassed and purged with nitrogen for 10 min. Pd(dppf)Cl₂ (8 mg,0.00985 mmol) was added, and the RM was again degassed and purged withnitrogen for another 5 min, then heated to 80° C. in a sealed tubeovernight. The RM was allowed to cool to rt and diluted with chloroform.The organic layer was concentrated to get the crude product, which waspurified through flash chromatography by using 100-200 mesh silica gel.The compound was eluted at 40% ethyl acetate in hexane as half whitecolored solid compound 293.

Step 3:

To a solution of 293 (60 mg, 0.9836 mmol) in methanol (20 mL) and water(8 mL) was added potassium carbonate (40 mg, 0.295 mmol). The RM washeated to 60° C. overnight. The solvent was completely distilled off andthe remainder diluted with water (25 mL) and extracted with chloroformtwice (2×25 mL). The combined organic layer was dried over sodiumsulphate, filtered and concentrated to get the crude compound, which waspurified through flash chromatography by using 100-200 mesh silica gel.The compound was eluted at 60% ethyl acetate in hexane as pale yellowsolid compound 294. ¹HNMR (400 MHz, CDCl₃): 9.75 (s, 1H), 8.66 (d, 1H),8.39 (d, 1H), 7.81 (d, 1H), 7.49 (d, 1H), 7.20 (m, 2H), 7.00 (d, 1H),6.93 (d, 1H), 3.74 (m, 6H), 2.55 (m, 4H) MS-ES+ 456.1

Preparation of Example 1954-(5-(3-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazol-2-yl)morpholine(296)

Step 1:

To a solution of 292 (100 mg, 0.197 mmol) and 269 (42 mg, 0.197 mmol) inacetonitrile (5 mL) was added cesium carbonate (128 mg, 0.394 mmol). TheRM was degassed and purged with nitrogen for 10 min. Pd(dppf)Cl₂ (8 mg,0.00985 mmol) was added and the RM was again degassed and purged withnitrogen for another 5 min. The RM was heated to 80° C. in a sealed tubeovernight, then allowed to cool to rt and diluted with chloroform. Theorganic layer was concentrated to get the crude product, which waspurified through flash chromatography by using 100-200 mesh silica gel.The compound was eluted at 40% ethyl acetate in hexane as half whitecolored solid compound 295.

Step 2:

To a solution of 295 (60 mg, 0.1005 mmol) in methanol (20 mL) and water(5 mL) was added potassium carbonate (41 mg, 0.3016 mmol). The RM washeated to 60° C. overnight. The solvent was completely distilled off andthe remainder diluted with water (25 mL) and extracted with chloroformtwice (2×25 mL). The combined organic layer was dried over sodiumsulphate, filtered and concentrated to get the crude compound. The crudewas purified through flash chromatography by using 100-200 mesh silicagel. The compound was eluted at 70% ethyl acetate in hexane as paleyellow solid compound 296. ¹HNMR (400 MHz, CDCl₃): 9.51 (bs, 1H), 8.52(d, 1H), 8.23 (d, 1H), 7.77 (d, 1H), 7.44 (m, 2H), 7.20 (t, 1H), 7.00(d, 1H), 3.84 (m, 4H), 3.53 (m, 4H). MS-ES+ 443.09

Preparation of Example 196 N-(tertbutyl)-3-(3-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methylbenzene-sulfonamide(298)

Step 1:

To a solution of compound 292 (100 mg, 0.1971 mmol) and 178 (0.53 mg,0.197 mol) in acetonitrile (5 mL) was added cesium carbonate (128 mg,0.3942 mmol). The reaction was degassed and purged with nitrogen for 10min and charged with Pd(dppf)Cl₂ (8 mg, 0.009856 mmol). The reaction wasagain degassed and purged with nitrogen for another 5 min. The reactionwas heated to 80° C. in a sealed tube overnight, allowed to cool to rt,and diluted with chloroform. The organic layer was concentrated to getthe crude. The crude was purified through flash chromatography by using100-200 mesh silica gel. The compound was eluted at 35% ethyl acetate inhexane as half white coloured solid compound 297.

Step 2:

To a solution of 297 (70 mg, 0.10707 mmol) in methanol (20 mL) and water(5 mL) was added potassium carbonate (44 mg, 0.3212 mmol). The reactionwas heated to 60° C. overnight. The solvent was completely distilled offand the remainder diluted with water (25 mL) and extracted withchloroform twice (2×25 mL). The combined organic layer was dried oversodium sulphate, filtered and concentrated to get the crude, which waspurified through flash chromatography by using neutral alumina. Thecompound was eluted at 2% methanol in chloroform as half white solid298. ¹H NMR (CDCl₃) δ: 9.66 (bs, 1H), 8.64 (bs, 1H), 8.41 (d, 1H), 8.10(m, 1H), 7.83 (m, 3H), 7.59 (m, 1H), 7.49 (m, 1H), 7.21 (m, 1H), 7.01(m, 1H), 3.02 (s, 3H), 1.39 (s, 9H) and MS m/z=500.1 (M+H).

Preparation of Example 1973-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-5-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridine(300)

Step 1:

To a solution of compound 292 (100 mg, 0.1971 mmol) and 264 (57 mg,0.1971 mmol) in acetonitrile (5 mL) was added cesium carbonate (128 mg,0.3942 mmol). The reaction was degassed and purged with nitrogen for 10min. Pd (dppf) Cl₂ (8 mg, 0.00985 mmol) was added to the reaction, whichwas again degassed and purged with nitrogen for another 5 min. Thereaction was heated to 80° C. in a sealed tube overnight, allowed tocool to rt and diluted with chloroform. The organic layer wasconcentrated to get the crude, which was purified through flashchromatography by using 100-200 mesh silica gel. Eluting at 40% ethylacetate in hexane gave a half white coloured solid 299.

Step 2:

To a solution of 299 (60 mg, 0.101 mmol) in methanol (20 mL) and water(5 mL) was added potassium carbonate (41 mg, 0,303 mmol). The reactionwas heated to 60° C. overnight. The solvent was completely distilled offand the remainder diluted with water (25 mL), and extracted withchloroform twice (2×25 mL). The combined organic layer was dried oversodium sulphate, filtered, and concentrated to get the crude, which waspurified through flash chromatography by using neutral alumina. Thecompound was eluted at 0.5% methanol in chloroform as pale brown solidcompound 300. ¹H NMR (CDCl₃) δ: 9.50 (bs, 1H), 8.65 (d, 1H), 8.39 (d,1H), 7.79 (d, 1H), 7.49 (dd, 1H), 7.20 (m, 2H), 6.99 (dd, 1H), 6.92 (d,1H), 3.86 (s, 2H), 2.63 (m, 4H), 1.83 (m, 4H) and MS m/z=440.0 (M+H).

Preparation of Example 1983-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-5-(5-(piperidin-1-ylmethyl)thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridine(302)

Step 1:

To a solution of compound 292 (100 mg, 0.1971 mmol) and 264 (0.53 mg,0.197 mmol) in acetonitrile (5 mL) was added cesium carbonate (128 mg,0.3942 mmol). The reaction was degassed and purged with nitrogen for 10min and Pd (dppf) Cl₂ (8 mg, 0.009856 mmol) was added to the reaction,which was again degassed and purged with nitrogen for another 5 min. Thereaction was heated to 80° C. in a sealed tube overnight. The reactionwas allowed to cool to rt and diluted with chloroform. The organic layerwas concentrated to get the crude, which was purified through flashchromatography by using 100-200 mesh silica gel. The compound was elutedat 40% ethyl acetate in hexane as half white coloured solid 301.

Step 2:

To a solution of 301 (60 mg, 0.0987 mmol) in methanol (20 mL) and water(5 mL) was added potassium carbonate (40 mg, 0.2963 mmol). The reactionwas heated to 60° C. overnight. The solvent was completely distilledoff, the remainder diluted with water (25 mL), and extracted withchloroform twice (2×25 mL). The combined organic layer was dried oversodium sulphate filtered and concentrated to get the crude, which waspurified through flash chromatography by using neutral alumina. Thecompound was eluted at 1.5% methanol in chloroform as pale yellow solid302. ¹H NMR (CDCl₃) δ: 9.53 (bs, 1H), 8.66 (d, 1H), 8.39 (d, 1H), 7.79(d, 1H), 7.49 (d, 1H), 7.20 (m, 2H), 7.00 (d, 1H), 6.90 (d, 1H), 3.71(s, 2H), 2.48 (bs, 4H), 1.63 (m, 4H), 1.45 (m, 2H) and MS m/z=454.1(M+H).

Preparation of Example 1994-(4-(3-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazol-2-yl)morpholine(306)

Step 1:

To a solution of 292 (400 mg, 0.788 mmol) in DMF was added potassiumacetate (154 mg, 1.576 mmol) and bispinacalatodiborane (400 mg, 1.576mmol). The reaction mixture was degassed and purged with nitrogen for 10min. Pd (pph3)₂Cl₂ (27 mg, 0.03942 mmol) was added and again degassedand purged with nitrogen for 10 min. The reaction was heated to 100° C.for 2 h. After completion of the reaction, the RM was diluted withchloroform and washed with cold water followed by Brine solution. Theorganic layer was dried over sodium sulphate and evaporated to get thecrude, which was triturated with Hexane to afford a brown solid3-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine303 taken up for next step without further purification.

Step 2:

To a solution of 303 (438 mg, 0.786 mmol) and 304 (196 mg, 0.786 mmol)in acetonitrile (10 mL) was added cesium carbonate (512 mg, 0.157 mmol).The reaction was degassed and purged with nitrogen for 10 min. Pd (dppf)Cl₂ (32 mg, 0.0393 mmol) was added to the reaction, which was againdegassed and purged with nitrogen for another 5 min. The reaction washeated to 80° C. in a sealed tube overnight. The reaction was allowed tocool to rt and diluted with chloroform. The organic layer wasconcentrated to get the crude, which was purified through flashchromatography by using 100-200 mesh silica gel. The compound was elutedat 40% ethyl acetate in hexane as half white coloured solid 305.

Step 3:

To a solution of 305 (200 mg, 0.335 mmol) in methanol (20 mL) and water(5 mL) was added potassium carbonate (138 mg, 1.01005 mmol). Thereaction was heated to 60° C. overnight. The solvent was completelydistilled off and the remainder diluted with water (25 mL) and extractedwith chloroform twice (2×25 mL). The combined organic layer was driedover sodium sulphate, filtered and concentrated to get the crude, whichwas purified through flash chromatography by using 100-200 mesh silicagel. The compound was eluted at 5% methanol in chloroform as pale yellowsolid4-(4-(3-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazol-2-yl)morpholine306. ¹H NMR (CDCl₃) δ: 12.30 (s, 1H), 8.87 (d, 1H), 8.67 (d, 1H, 7.95(d, 1H), 7.61 (m, 1H), 7.41 (s, 1H), 7.31 (m, 2H), 3.73 (m, 4H), 3.45(m, 4H) and MS m/z=443.0 (M+H).

Preparation of Example 200(4-((5-(3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiophen-2-yl)methyl)morpholine(309)

Step 1:

To a solution of 307 (100 mg, and 0.197 mmol) and 236 (60 mg, 0.197mmol) in acetonitrile (5 mL) was added cesium carbonate (128 mg, 0.3942mmol). The reaction was degassed and purged with nitrogen for 10 min. Pd(dppf) Cl₂ (8 mg, 0.00985 mmol) was added to the reaction, which wasagain degassed and purged with nitrogen for another 5 min. The reactionwas heated to 80° C. in a sealed tube overnight, allowed to cool to rt,and diluted with chloroform. The organic layer was concentrated to getthe crude, which was purified through flash chromatography by using100-200 mesh silica gel. The compound was eluted at 50% ethyl acetate inhexane as half white coloured solid 308.

Step 2:

To a solution of 308 (70 mg, 0.1148 mmol) in methanol (20 mL) and water(5 mL) was added potassium carbonate (47 mg, 0.344 mmol). The reactionwas heated to 60° C. overnight. The solvent was completely distilled offand the remainder diluted with water (25 mL) and extracted withchloroform twice (2×25 mL). The combined organic layer was dried oversodium sulphate, filtered and concentrated to get the crude, which waspurified through flash chromatography by using neutral alumina. Thecompound was eluted at 2% methanol in dichloromethane as pale yellowsolid4-((5-(3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiophen-2-yl)methyl)morpholine309. ¹H NMR (CDCl₃) δ: 9.13 (s, 1H), 8.63 (d, 1H), 8.25 (d, 1H), 7.45(d, 1H), 7.32 (m, 2H), 7.15 (m, 2H), 6.92 (d, 1H), 3.75 (m, 4H), 3.73(m, 2H), 2.55 (m, 4H) and MS m/z=454.1 (M+H).

Preparation of Example 2014-(5-(3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazol-2-yl)morpholine(311)

Step 1:

A solution of 307 (100 mg, 0.1971 mmol) and 269 (58 mg, 0.01971 mmol) inacetonitrile (5 mL) was added cesium carbonate (128 mg, 0.3942 mmol).The reaction was degassed and purged with nitrogen for 10 min. Pd (dppf)Cl₂ (8 mg, 0.009856 mmol) was added to the reaction, which was againdegassed and purged with nitrogen for another 5 min. The reaction washeated to 80° C. in a sealed tube overnight, allowed to cool to rt anddiluted with chloroform. The organic layer was concentrated to get thecrude, which was purified through flash chromatography by using 100-200mesh silica gel. The compound was eluted at 30% ethyl acetate in hexaneas half white coloured solid 310.

Step 2:

To a solution of 310 (60 mg, 0.1005 mmol) in methanol (20 mL) and water(5 mL) was added potassium carbonate (41 mg, 0.30169 mmol). The reactionwas heated to 60° C. overnight. The solvent was completely distilled offand the remainder diluted with water (25 mL) and extracted withchloroform twice (2×25 mL). The combined organic layer was dried oversodium sulphate, filtered and concentrated to get the crude, which waspurified through flash chromatography by using neutral alumina. Thecompound was eluted at 70% ethyl acetate in hexane as a half white solid4-(5-(3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazol-2-yl)morpholine311. ¹H NMR (CDCl₃) δ: 9.19 (s, 1H), 8.51 (s, 1H), 8.09 (d, 1H), 7.45(m, 2H), 7.30 (m, 2H), 7.15 (d, 1H), 3.84 (m, 4H), 3.53 (m, 4H) and MSm/z=443.0 (M+H).

Preparation of Example 202N-(tert-butyl)-3-(3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methylbenzenesulfonamide (313)

Step 1:

To a solution of 307 (100 mg, 0.1971 mmol) and 178 (53 mg, 0.1971 mmol)in acetonitrile (5 mL) was added cesium carbonate (128 mg, 0.3942 mmol).The reaction was degassed and purged with nitrogen for 10 min. Pd (dppf)Cl₂ (8 mg, 0.009856 mmol) was added to the reaction, which was againdegassed and purged with nitrogen for another 5 min. The reaction washeated to 80° C. in a sealed tube overnight, allowed to cool to rt anddiluted with chloroform. The organic layer was concentrated to get thecrude, which was purified through flash chromatography by using 100-200mesh silica gel. The compound was eluted at 46% ethyl acetate in hexaneas half white coloured solid 313.

Step 2:

To a solution of 313 (70 mg, 0.10708 mmol) in methanol (20 mL) and water(5 mL) was added potassium carbonate (44 mg, 0.3212 mmol). The reactionwas heated to 60° C. overnight. The solvent was completely distilled offand the remainder diluted with water (25 mL) and extracted withchloroform twice (2×25 mL). The combined organic layer was dried oversodium sulphate, filtered and concentrated to get the crude, which waspurified through flash chromatography by using 100-200 mesh silica gel.The compound was eluted at 1.5% methanol in chloroform as pale yellowsolidN-(tert-butyl)-3-(3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-Nmethylbenzene-sulphonamide 313. ¹H NMR (CDCl₃) δ: 9.44 (s, 1H), 8.61 (d,1H), 8.29 (d, 1H), 8.08 (d, 1H), 7.81 (m, 2H), 7.60 (t, 1H), 7.52 (m,1H), 7.34 (m, 2H), 7.16 (d, 1H), 3.01 (s, 3H), 1.39 (s, 9H) and MS ES+500.1.

Preparation of Example 2033-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-5-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridine(315)

Step 1:

To a solution of 292 (100 mg, 0.0001971 mmol) and 264 (58 mg, 0.1971mmol) in acetonitrile (5 mL) was added cesium carbonate (128 mg, 0.3942mmol). The reaction was degassed and purged with nitrogen for 10 min andPd (dppf) Cl₂ DCM (8 mg, 0.00985 mmol) was added to the reaction, whichwas again degassed and purged with nitrogen for another 5 min. Thereaction was heated to 80° C. in a sealed tube overnight, allowed tocool to rt and diluted with chloroform. The organic layer wasconcentrated to get the crude, which was purified through flashchromatography by using 100-200 mesh silica gel. The compound was elutedat 36% ethyl acetate in hexane as half white coloured solid compound314.

Step 2:

To a solution of 314 (60 mg, 0.101 mml) in methanol (20 mL) and water (5mL) was added potassium carbonate (41 mg, 0.303 mmol). The reaction washeated to 60° C. overnight. The solvent was completely distilled off andthe remainder diluted with water (25 mL) and extracted with chloroformtwice (2×25 mL). The combined organic layer was dried over sodiumsulphate, filtered and concentrated to get the crude, which was purifiedthrough flash chromatography by using 100-200 mesh silica gel. Thecompound was eluted at 3% Methanol in chloroform as half white solid3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-5-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridine315. ¹H NMR (CDCl₃) δ: 9.27 (s, 1H), 8.63 (d, 1H), 8.26 (d, 1H) 7.45 (d,1H), 7.34 (m, 2H), 7.16 (m, 2H), 6.91 (d, 1H), 3.85 (s, 2H), 2.62 (bs,4H), 1.83 (bs, 4H) MS ES+ 440.0.

Preparation of Example 2043-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-5-(5-(piperidin-1-ylmethyl)thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridine(318)

Step 1:

To a solution of 307 (100 mg, 0.1971 mmol) and 316 (60 mg, 0.1971 mmol)in acetonitrile (5 mL) was added cesium carbonate (128 mg, 0.3942 mmol).The reaction was degassed and purged with nitrogen for 10 min. Pd (dppf)Cl₂ (8 mg, 0.00985 mmol) was added to the reaction, which was againdegassed and purged with nitrogen for another 5 min. The reaction washeated to 80° C. in a sealed tube overnight, allowed to cool to rt anddiluted with chloroform. The organic layer was concentrated to get thecrude, which was purified through flash chromatography by using 100-200mesh silica gel. The compound was eluted at 45% ethyl acetate in hexaneas half white coloured solid 317.

Step 2:

To a solution of 317 (60 mg, 0.0987 mmol) in methanol (20 mL) and water(5 mL) was added potassium carbonate (40 mg, 0.2962 mmol). The reactionwas heated to 60° C. overnight. The solvent was completely distilled offand the remainder diluted with water (25 mL) and extracted withchloroform twice (2×25 mL). The combined organic layer was dried oversodium sulphate, filtered and concentrated to get the crude. The crudewas purified through flash chromatography by using neutral alumina. Thecompound was eluted at 0.5% methanol in dichloromethane as pale yellowsolid3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-5-(5-(piperidin-1-ylmethyl)thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridine318. ¹H NMR (CDCl₃) δ: 9.29 (s, 1H), 8.63 (d, 1H), 8.26 (d, 1H), 7.45(d, 1H), 7.32 (m, 2H), 7.15 (m, 2H), 6.89 (d, 1H), 3.70 (s, 2H), 2.47(s, 4H), 1.61 (m, 4H), 1.25 (m, 2H) and MS ES+ 454.1.

Preparation of Example 2054-(4-(3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazol-2-yl)morpholine(321)

Step 1:

To a solution of 307 (400 mg, 0.788 mmol) in DMF was added potassiumacetate (154 mg, 1.576 mmol) and bispinacalatodiborane (400 mg, 1.576mmol). The reaction mixture was degassed and purged with nitrogen for 10min. Pd (pph3)₂ Cl₂ (27 mg, 0.03942 mmol) was added and again degassedand purged with nitrogen for 10 min. The reaction was heated to 100° C.for 2 h. After completion of the reaction the RM was diluted withchloroform and washed with cold water followed by Brine solution. Theorganic layer was dried over sodium sulphate and evaporated to get thecrude, which was triturated with Hexane to afford brown solid 319. Thesolid itself proceeded for next step without further purification.

Step 2:

To a solution of 319 (438 mg, 0.786 mmol) and 304 (196 mg, 0.786 mmol)in acetonitrile (10 mL) was added cesium carbonate (512 mg, 0.157 mmol).The reaction was degassed and purged with nitrogen for 10 min. Pd (dppf)Cl₂ (32 mg, 0.0393 mmol) was added to the reaction, which was againdegassed and purged with nitrogen for another 5 min. The reaction washeated to 80° C. in a sealed tube overnight, allowed to cool to rt anddiluted with chloroform. The organic layer was concentrated to get thecrude, which was purified through flash chromatography by using 100-200mesh silica gel. The compound was eluted at 40% ethyl acetate in hexaneas half white coloured solid 320.

Step 3:

To a solution of 320 (200 mg, 0.335 mmol) in methanol (20 mL) and water(5 mL) was added potassium carbonate (138 mg, 1.01005 mmol). Thereaction was heated to 60° C. overnight. The solvent was completelydistilled off and the remainder diluted with water (25 mL) and extractedwith chloroform twice (2×25 mL). The combined organic layer was driedover sodium sulphate, filtered and concentrated to get the crude, whichwas purified through flash chromatography by using 100-200 mesh silicagel. The compound was eluted at 5% methanol in chloroform as pale yellowsolid4-(4-(3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazol-2-yl)morpholine321. ¹H NMR (CDCl₃) δ: 10.05 (s, 1H), 8.84 (s, 1H), 8.53 (s, 1H), 7.44(d, 1H), 7.34 (d, 3H), 7.14 (d, 1H), 6.83 (s, 1H), 3.85 (t, 4H), 3.55(t, 4H) and MS ES+ 443.00.

Preparation of Example 2063-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine(324)

Step 1:

To a solution of 307 (100 mg, 0.1971 mmol) and 278 (74 mg, 0.1971 mmol)in acetonitrile (5 mL) was added cesium carbonate (128 mg, 0.3942 mmol).The reaction was degassed and purged with nitrogen for 10 min and Pd(dppf) Cl₂ (8 mg, 0.00985 mmol) was added to the reaction, which wasagain degassed and purged with nitrogen for another 5 min. The reactionwas heated to 80° C. in a sealed tube overnight, allowed to cool to rtand diluted with chloroform. The organic layer was concentrated to getthe crude, which was purified through flash chromatography by using100-200 mesh silica gel. The compound was eluted at 40% ethyl acetate inhexane as half white coloured solid 322.

Step 2:

To a solution of 322 (70 mg, 0.1033 mmol) in methanol (20 mL) and water(5 mL) was added potassium carbonate (42 mg, 0.31009 mmol). The reactionwas heated to 60° C. overnight. The solvent was completely distilled offand the remainder diluted with water (25 mL) and extracted withchloroform twice (2×25 mL). The combined organic layer was dried oversodium sulphate, filtered and concentrated to get the crude, which waspurified through flash chromatography by using 100-200 mesh silica gel.The compound was eluted at 70% ethyl acetate in Hexane as pale yellowsolid 323.

Step 3:

A solution of 323 (0.050 mg, 0.0955 mmol) in CHCl₃ (20 mL) was taken andadded TFA (5 mL) at rt. The reaction mixture was stirred for 2 h at rt.After confirmation of TLC, the reaction mixture evaporated TFAcompletely then taken in CHCl₃ and washed with Na₂CO₃ solution followedby water wash. Organic layer was dried with Na₂SO₄ and evaporated. Theresulting crude was purified via silica gel chromatography using agradient of 3% methanol in chloroform to afford pale brown solid3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine324. ¹H NMR (CDCl₃) δ: 11.94 (s, 1H), 8.55 (d, 1H), 8.40 (s, 1H), 8.34(s, 1H), 7.99 (s, 1H), 7.89 (s, 1H), 7.79 (s, 1H), 7.59 (d, 1H), 7.44(d, 1H), 4.17 (m, 1H), 3.04 (m, 2H), 2.57 (m, 2H), 1.98 (m, 2H), 1.81(m, 2H) and MS ES+ 424.0.

Preparation of Example 2074-(4-(3-(3-fluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazol-2-yl)morpholine(327)

Step 1:

To a solution of 122 (400 mg, 0.8415 mmol) in DMF was added potassiumacetate (165 mg, 1.683 mmol) and bispinacalatodiborane (427 mg, 1.683mmol). The reaction mixture was degassed and purged with nitrogen for 10min and Pd(pph3)₂Cl₂ (29 mg, 0.0427 mmol) was added, again degassed andpurged with nitrogen for 10 min. The reaction was heated to 100° C. for2 h. After completion of the reaction, the RM was diluted withchloroform and washed with cold water followed by brine solution. Theorganic layer was dried over sodium sulphate and evaporated to get thecrude, which was triturated with hexane to afford brown solid. The soliditself was used in the next step without further purification.

Step 2:

To a solution of 325 (441 mg, 0.841 mmol) and 304 (209 mg, 0.841 mmol)in acetonitrile (10 mL) was added cesium carbonate (547 mg, 1.681 mmol).The reaction was degassed and purged with nitrogen for 10 min.Pd(dppf)Cl₂ DCM (34 mg, 0.04203 mmol) was added to the reaction, whichwas again degassed and purged with nitrogen for another 5 min. Thereaction was heated to 80° C. in a sealed tube overnight, allowed tocool to rt, and diluted with chloroform. The organic layer wasconcentrated to get the crude, which was purified through flashchromatography by using 100-200 mesh silica gel. The compound was elutedat 40% ethyl acetate in hexane as half white coloured solid 326.

Step 3:

To a solution of 326 (200 mg, 0.335 mmol) in methanol (20 mL) and water(5 mL) was added potassium carbonate (138 mg, 1.0056 mml). The reactionwas heated to 60° C. overnight. The solvent was completely distilled offand the remainder diluted with water (25 mL) and extracted withchloroform twice (2×25 mL). The combined organic layer was dried oversodium sulphate, filtered and concentrated to get the crude, which waspurified through flash chromatography by using 100-200 mesh silica gel.The compound was eluted at 5% methanol in chloroform as pale yellowsolid4-(4-(3-(3-fluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazol-2-yl)morpholine327. ¹H NMR (400 MHz, CDCl3) δ: 9.52 (s, 1H), 8.86 (s, 1H), 8.54 (s,1H), 7.68 (s, 1H), 7.38 (d, 1H), 7.07 (m, 2H), 6.82 (s, 1H), 3.85 (t,4H), 3.75 (s, 3H), 3.55 (t, 4H) and MS ES+ 411.0.

Preparation of Example 2084-(4-(3-(3,5-difluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazol-2-yl)morpholine(329)

Step 1:

To a solution of 155 (40 mg, 0.08108 mmol) and 269 (24 mg, 0.08108 mmol)in acetonitrile (5 mL) was added cesium carbonate (52 mg, 0.161 mmol).The reaction was degassed and purged with nitrogen for 10 min.Pd(dppf)Cl₂ (3 mg, 0.04054 mmol) was added to the reaction, which wasagain degassed and purged with nitrogen for another 5 min. The reactionwas heated to 80° C. in a sealed tube overnight, allowed to cool to rt,and diluted with chloroform. The organic layer was concentrated to getthe crude, which was purified through flash chromatography by using100-200 mesh silica gel. The compound was eluted at 40% ethyl acetate inhexane as half white coloured solid 328.

Step 2:

To a solution of 328 (25 mg, 0.0429 mmol) in methanol (20 mL) and water(5 mL) was added potassium carbonate (17 mg, 0.107 mmol). The reactionwas heated to 60° C. overnight. The solvent was completely distilled offand the remainder diluted with water (25 mL) and extracted withchloroform twice (2×25 mL). The combined organic layer was dried oversodium sulphate, filtered and concentrated to get the crude, which waspurified through flash chromatography by using neutral alumina. Thecompound was eluted at 1.5% methanol in chloroform as pale yellow solid4-(4-(3-(3,5-difluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazol-2-yl)morpholine329. ¹H NMR (400 MHz, CDCl₃) δ: 9.46 (s, 1H), 8.87 (s, 1H), 8.54 (s,1H), 7.73 (s, 1H), 7.14 (s, 1H), 6.84 (m, 2H), 3.85 (m, 4H), 3.69 (s,3H), 3.57 (m, 4H) and MS ES+ 429.0.

Preparation of Example 2093-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine(332)

Step 1:

To a solution of 292 (100 mg, 0.1971 mmol) and 278 (74 mg, 0.1971 mmol)in acetonitrile (5 mL) was added cesium carbonate (128 mg, 0.3942 mmol).The reaction was degassed and purged with nitrogen for 10 min.Pd(dppf)Cl₂ (8 mg, 0.00985 mmol) was added to the reaction, which wasagain degassed and purged with nitrogen for another 5 min. The reactionwas heated to 80° C. in a sealed tube overnight, allowed to cool to rt,and diluted with chloroform. The organic layer was concentrated to getthe crude, which was purified through flash chromatography by using100-200 mesh silica gel. The compound was eluted at 40% ethyl acetate inhexane as half white coloured solid 330.

Step 2:

To a solution of 330 (70 mg, 0.1033 mmol) in methanol (20 mL) and water(5 mL) was added potassium carbonate (42 mg, 0.31009 mmol). The reactionwas heated to 60° C. overnight. The solvent was completely distilled offand the remainder diluted with water (25 mL) and extracted withchloroform twice (2×25 mL). The combined organic layer was dried oversodium sulphate, filtered and concentrated to get the crude, which waspurified through flash chromatography by using 100-200 mesh silica gel.The compound was eluted at 70% ethyl acetate in hexane as pale yellowsolid 331.

Step 3:

A solution of 331 (0.050 gm, 0.0955 mmol) in CHCl₃ (20 mL) was taken andadded TFA (5 mL) at rt. The reaction mixture was stirred for 2 hr at rt.After TLC confirmation, the RM was evaporated TFA completely then takenin CHCl₃ and washed with Na₂CO₃ solution followed by water wash. Organiclayer was dried with Na₂SO₄ and evaporated. The resulting crude waspurified via silica gel chromatography using a gradient of 3% methanolin chloroform to afford pale brown solid3-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine332. ¹H NMR (400 MHz, CDCl3) δ: 9.90 (s, 1H), 8.59 (d, 1H), 8.29 (d,1H), 7.89 (s, 1H), 7.84 (d, 1H), 7.77 (d, 1H), 7.49 (dd, 1H), 7.18 (t,1H), 7.00 (dd, 1H), 4.29 (m, 1H), 3.29 (d, 2H), 2.80 (m, 2H), 2.21 (m,2H), 2.03 (m, 2H) and MS ES+ 424.0.

Preparation of Example 2123-(3,5-difluoro-2-methoxyphenyl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine(334)

Step 1:

A solution of 281 (300 mg, 0.451 mmol) in CHCl₃ (20 mL) was taken andadded TFA (5 mL) at rt. The reaction mixture was stirred for 2 h at rt.After TLC confirmation, RM evaporated TFA completely, then taken inCHCl₃ and washed with Na₂CO₃ solution followed by water wash. Organiclayer was dried with Na₂SO₄ and evaporated. The resulting crude waspurified via silica gel chromatography using a gradient of 3% methanolin chloroform to afford pale brown solid 282.

Step 2:

A solution of 282 (150 mg, 0.266 mmol) in acetonitrile was taken and addpotassium carbonate (73 mg, 0.5322 mmol) and methyl iodide (56 mg, 0.399mmol). The RM was stirred at 80° C. overnight. After completion of thereaction the RM was diluted with chloroform and filtered off the solids.The organic layer was evaporated to dryness. The resulting crude waspurified via silica gel chromatography using 4% methanol in chloroformto afford off white solid 333.

Step 3:

To a solution of 333 (0.1731 mmol) in methanol (20 mL) and water (5 mL)was added potassium carbonate (71 mg, 0.5193 mmol). The reaction washeated to 60° C. overnight. The solvent was completely distilled off andthe remainder diluted with water (25 mL) and extracted with chloroformtwice (2×25 mL). The combined organic layer was dried over sodiumsulphate, filtered and concentrated to get the crude, which was purifiedthrough flash chromatography by using 100-200 mesh silica gel. Thecompound was eluted at 5% methanol in chloroform as pale yellow solid3-(3,5-difluoro-2-methoxyphenyl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine334. ¹H NMR (400 MHz, DMSO) δ: 12.08 (s, 1H), 8.57 (d, 1H), 8.43 (s,1H), 8.18 (d, 1H), 8.02 (s, 1H), 7.82 (d, 1H), 7.23 (m, 2H), 4.46 (m,1H), 3.55 (m, 7H), 3.17 (d, 6H), 2.32 (m, 4H) and MS ES+ 424.10.

Preparation of Example 2143-(3,5-difluoro-2-methoxyphenyl)-5-(1-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine(336)

Step 1:

To a solution of 282 (100 mg, 0.244 mmol) in DCM was added triethylamine(49 mg, 0.4887 mmol). Methanesulfonyl chloride 335 (41 mg, 0.3665 mmol)was added to the reaction and stirred for 2 h at rt. The reactionmixture was diluted with dichloromethane and washed with water twice.The organic layer was dried over sodium sulphate and concentrated to getthe crude, which was purified by flash column using 100-200 mesh silicagel. The compound was eluted at 2% methanol in chloroform as off whitecoloured solid3-(3,5-difluoro-2-methoxyphenyl)-5-(1-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1Hpyrrolo[2,3-b]pyridine 336. ¹H NMR (400 MHz, DMSO) δ: 12.05 (s, 1H),8.55 (d, 1H), 8.30 (s, 1H), 8.19 (d, 1H), 7.97 (s, 1H), 7.82 (d, 1H),7.24 (m, 2H), 4.33 (m, 1H), 3.65 (d, 2H), 3.60 (s, 3H), 2.94, (m, 2H),2.92 (s, 3H), 2.03 (m, 2H), 1.98 (m, 2H) and MS ES+ 488.0.

Preparation of Example 2153-(3,5-difluoro-2-methoxyphenyl)-5-(1-(1-(ethylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine(338)

Step 1:

To a solution of 282 (100 mg, 0.244 mmol) in DCM was added triethylamine(49 mg, 0.4887 mmol). Ethane sulfonyl chloride 337 (47 mg, 0.3665 mmol)was added to the reaction and stirred it for 2 h at rt. The reactionmixture was diluted with dichloromethane and washed with water twice.The organic layer was dried over sodium sulphate and concentrated to getthe crude, which was purified by flash column using 100-200 mesh silicagel. The compound was eluted at 2% methanol in chloroform as off whitecoloured solid3-(3,5-difluoro-2-methoxyphenyl)-5-(1-(1-(ethylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine338. ¹H NMR (400 MHz, CDCl3) δ: 9.58 (s, 1H), 8.52 (d, 1H), 8.17 (d,1H), 7.84 (s, 1H), 7.72 (m, 2H), 7.09 (m, 1H), 6.82 (m, 1H), 4.31 (m,1H), 3.96 (m, 2H), 3.68 (s, 3H), 3.06 (m, 2H), 3.00 (m, 3H), 2.29 (m,2H), 2.14 (m, 2H), 1.40 (m, 5H), 1.25 (m, 5H) and MS ES+ 502.1.

Preparation of Example 2163-(3,5-difluoro-2-methoxyphenyl)-5-(1-(1-(propylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine(340)

Step 1:

To a solution of 282 (100 mg, 0.244 mmol) in DCM was added triethylamine(49 mg, 0.4887 mmol). Propane sulfonyl chloride 339 (52 mg, 0.366 mmol)was added to the reaction and stirred for 2 h at rt. The reactionmixture was diluted with dichloromethane and washed with water twice.The organic layer was dried over sodium sulphate and concentrated to getthe crude, which was purified by flash column using 100-200 mesh silicagel. The compound was eluted at 2% methanol in chloroform as off whitecoloured solid3-(3,5-difluoro-2-methoxyphenyl)-5-(1-(1-(propylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine340. ¹H NMR (400 MHz, CDCl3) δ: 9.68 (s, 1H), 8.53 (d, 1H), 8.17 (d,1H), 7.84 (s, 1H), 7.73 (m, 2H), 7.09 (m, 1H), 6.82 (m, 1H), 4.31 (m,1H), 3.95 (m, 2H), 3.68 (d, 3H), 3.01 (m, 2H), 2.94 (m, 2H), 2.36 (m,2H), 2.14 (m, 2H), 1.86 (m, 2H), 1.06 (m, 3H) and MS ES+ 516.1.

Preparation of Example 2203-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine(341)

To a solution of 324 (50 mg, 0.1182 mmol) in DCM was added triethylamine(17.9 mg, 0.236 mmol). Methyl iodide (18.3 mg, 0.130 mmol) was added tothe reaction and stirred for 2 h at rt. The reaction mixture was dilutedwith dichloromethane and washed with water twice. The organic layer wasdried over sodium sulphate and concentrated to get the crude, which waspurified by flash column using 100-200 mesh silica gel. The compound waseluted at 2% methanol in chloroform as off white coloured solid3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine341.

Preparation of Example 2213-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-5-(1-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine(343)

Step 1:

To a solution of 324 (50 mg, 0.1182 mmol) in DCM was added triethylamine(17.9 mg, 0.1773 mmol). Methane sulfonyl chloride 342 (13.5 mg, 0.1182mmol) was added to the reaction and stirred for 2 h at rt. The reactionmixture was diluted with dichloromethane and washed with water twice.The organic layer was dried over sodium sulphate and concentrated to getthe crude, which was purified by flash column using 100-200 mesh silicagel. The compound was eluted at 2% methanol in chloroform as off whitecoloured solid3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-5-(1-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine343. ¹H NMR (400 MHz, DMSO) δ: 11.94 (s, 1H), 8.55 (d, 1H), 8.39 (m,2H), 8.03 (s, 1H), 7.88 (d, 1H), 7.78 (d, 1H), 7.58 (m, 1H), 7.44 (d,1H), 4.31 (m, 1H), 3.66 (m, 2H), 2.95 (s, 3H), 2.16 (m, 2H), 2.01 (m,2H) and MS ES+ 502.1.

Preparation of Example 2223-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-5-(1-(1-(ethylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine(344)

Step 1:

To a solution of 324 (50 mg, 0.1182 mmol) in DCM was added triethylamine(17.9 mg, 0.1771 mmol). Ethane sulfonyl chloride 337 (15 mg, 0.1182mmol) was added to the reaction and stirred for 2 h at rt. The reactionmixture was diluted with dichloromethane and washed with water twice.The organic layer was dried over sodium sulphate and concentrated to getthe crude, which was purified by flash column using 100-200 mesh silicagel. The compound was eluted at 2% methanol in chloroform to give offwhite coloured solid3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-5-(1-(1-(ethylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine344. ¹HNMR (400 MHz, DMSO) δ: 11.95 (s, 1H), 8.55 (d, 1H), 8.39 (m, 2H),8.02 (s, 1H), 7.88 (d, 1H), 7.78 (d, 1H), 7.58 (m, 1H, 7.44 (d, 1H),4.33 (m, 1H), 3.71 (m, 2H), 3.04 (m, 4H), 2.14 (m, 2H), 1.97 (m, 2H),1.21 (m, 4H) and Ms ES+516.1.

Preparation of Example 2233-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-5-(1-(1-(propylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine(345)

Step 1:

To a solution of 324 (50 mg, 0.1182 mmol) in DCM was added triethylamine(17.9 mg, 0.1773 mmol) and propane sulfonyl chloride 339 (16.7 mg,0.1182 mmol) and stirred for 2 h at rt. The RM was diluted withdichloromethane and washed with water twice. The organic layer was driedover sodium sulphate and concentrated to get the crude, which waspurified by flash column using 100-200 mesh silica gel. The compound waseluted at 2% Methanol in chloroform as off white coloured solid 345.¹HNMR (400 MHz, DMSO) δ: 11.95 (s, 1H), 8.55 (d, 1H), 8.39 (m, 2H), 8.03(s, 1H), 7.88 (d, 1H), 7.78 (d, 1H), 7.58 (m, 1H), 7.44 (d, 1H), 4.35(m, 1H), 3.69 (m, 2H), 3.03 (m, 4H), 2.14 (m, 2H), 1.97 (m, 2H), 1.70(m, 2H), 1.00 (m, 3H) and MS ES+ 530.1.

Preparation of Example 2262-(4-(4-(3-(3,5-difluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanol(347)

Step 1:

To a solution of 282 (50 mg, 0.122 mmol) in acetone was added potassiumcarbonate (25 mg, 0.244 mmol) and 2-bromo ethanol (18.3 mg, 0.146 mmol)and stirred for 12 h at 60° C. The reaction was filtered through celitebed and washed with ethyl acetate. The organic layer was concentrated toget the crude, which was purified by neutral alumina and the compoundwas eluted at 2% methanol in chloroform as half white coloured solid2-(4-(4-(3-(3,5-difluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanol347. ¹HNMR (400 MHz, DMSO) δ: 12.04 (s, 1H), 8.54 (d, 1H), 8.31 (s, 1H),8.18 (d, 1H), 7.93 (s, 1H), 7.81 (d, 1H), 7.22 (m, 2H), 4.39 (m, 1H),4.10 (m, 1H), 4.00 (m, 1H), 3.60 (s, 3H), 3.50 (m, 2H), 2.96 (d, 2H),2.42 (m, 2H), 2.13 (m, 2H), 1.99 (m, 3H), 1.16 (t, 1H) and MS ES+ 454.0.

Preparation of Example 2272-(4-(4-(3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanol(348)

Step 1:

To a solution of 324 (50 mg, 0.118 mmol) in acetone was added potassiumcarbonate (32 mg, 0.236 mmol) and 2-bromo ethanol (17.7 mg, 0.141 mmol),and stirred for 12 h at 60° C. The reaction was filtered through celitebed and washed with ethyl acetate. The organic layer was concentrated toget the crude, which was purified by neutral alumina and the compoundwas eluted at 2% methanol in chloroform as half white coloured solid2-(4-(4-(3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanol348. ¹HNMR (400 MHz, DMSO) δ: 11.93 (s, 1H), 8.54 (d, 1H), 8.38 (m, 2H),7.99 (s, 1H), 7.88 (d, 1H), 7.78 (d, 1H), 7.58 (m, 1H), 7.43 (d, 1H),4.39 (m, 1H), 4.11 (m, 1H, 3.50 (m, 2H), 2.97 (d, 2H), 2.43 (m, 2H),2.14 (m, 2H), 1.96 (m, 4H) and MS ES+ 468.0.

Preparation of Example 2283-(3-fluoro-2-methoxyphenyl)-5-(5-(1-(piperidin-1-yl)ethyl)thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridine(349)

Step 1:

To a solution of 267 (50 mg, 0.386 mmol) in THF was added n-butyllithium (11 mg, 0.173 mmol). Methyl iodide (18.3 mg, 0.129 mmol) wasadded to the reaction and stirred for 2 h at −30° C. The RM was quenchedwith ammonium chloride solution and stirred for 15 min. The aqueousphase was extracted twice with ethyl acetate. The resulting organiclayer was dried over sodium sulphate and concentrated to get the crude,which was purified by flash column using 100-200 mesh silica gel. Thecompound was eluted at 2% methanol in chloroform as off white colouredsolid 268.

Step 2:

To a solution of 368 (30 mg, 0.0508 mmol) in methanol (20 mL) and water(5 mL) was added potassium carbonate (21 mg, 0.152 mmol). The reactionwas heated to 60° C. overnight. The solvent was completely distilled offand the remainder diluted with water (25 mL) and extracted withchloroform twice (2×25 mL). The combined organic layer was dried oversodium sulphate, filtered and concentrated to get the crude, which waspurified through flash chromatography by using neutral alumina. Thecompound was eluted at 5% methanol in chloroform as pale yellow solid(10 mg) compound3-(3-fluoro-2-methoxyphenyl)-5-(5-(1-(piperidin-1-yl)ethyl)thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridine349.

Pharmaceutical Salts

Hydrochloric acid salts of the foregoing compounds were prepared bysolubilizing the compound in a minimum of ethanol and a solution ofethanolic HCl 20% was added drop wise and the mixture stirred for 1 hourfollowed by addition of diethyl ether. A precipitated off-white solidhydrochloride was separated by filtration, washer with diethyl ether anddried. In certain embodiments, the invention contemplates the treatmentof diseases or patients using a compound, or a prodrug, tautomeric, anisomeric, pharmaceutically acceptable salt, N-oxide, or stereoisomericform thereof, having a structure of Formula I, IA and IB.Pharmaceutically acceptable salts are derivatives of the claimedcompounds wherein the parent compound is modified by making acid or basesalts thereof. Examples of pharmaceutically acceptable salts include,but are not limited to organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids. The pharmaceutically acceptable salts include the standardnon-toxic salts or the quaternary ammonium salts of the parent compoundformed, for example, from non-toxic inorganic or organic acids. Forexample, such non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic andisethionic salts. The pharmaceutically acceptable salts of the presentinvention can be synthesized from the parent compound which contains abasic or acidic moiety by established chemical methods. Such salts canbe prepared by reacting free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, EtOAc, ethanol, isopropanol, or acetonitrile arepreferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences. 18^(th) ed., Mack Publishing Company, Easton,Pa., 1990, p. 1445.

Additional Examples Usage Method

The subject matter disclosed herein relates to the substituted1H-Pyrrolo[2,3-b]pyridine and 1H-Pyrazolo[3,4-b]pyridine derivatives asinhibitors of SIK1 (SNF1LK)(SEQ ID NO: 10, SIK2 (SNF1LK, QIK)(SEQ ID NO:11) and SIK3 (QSK)(SEQ ID NO: 24). Pharmaceutical compositionscontaining the Formula I, IA and IB compounds and methods of using thecompounds or compositions to treat various types of diseases orconditions mediated by SIK family isoform (SIK1 (SEQ ID NO: 10), SIK2(SEQ ID NO: 11) and SIK3 (SEQ ID NO: 24)) such as for example, diseasestates associated with abnormal cell growth such as cancer, stroke,obesity and type II diabetes. Additionally these compounds andcompositions containing the compounds are employed to treat ovarian andbreast cancers. In addition, these compounds are important futuretherapeutic agents for the treatment of lung, prostate and testiculartumours cancers. Methods of making the compounds and pharmaceuticalsalts thereof are also described herein.

The in vivo efficacy of 1H-Pyrrolo[2,3-b]pyridine and1H-Pyrazolo[3,4-b]pyridine derivatives in an established human ovarianxenograft growth inhibition experiments conducted is described and incombination with taxane and paclitaxel drugs. The potent and selectivetwo SIK2 (SEQ ID NO: 11) inhibitors were administered orally in doseescalation in vivo experiments starting from 20, 40, 60 and 80 mg/Kgafter 2 weeks of sub-cutaneous SKOV3 ovarian cancer cells injection into32 female nu/nu mice.

In Vitro Inhibition Assay SIK2 Kinase Assay

Procedure: Enzyme was incubated with substrate peptide in reactionbuffer in the presence and absence of test compounds or Staurosporine.All additions were done on ice, followed by the addition of ATP mix.Wells were uniformly mixed using an Eppendorff plate shaker andincubated at 30° C. for 20 min, and stopped by the addition of 5 μL of3% phosphoric acid. Volume was increased to 100 μL by adding 0.8%phosphoric acid which was then transferred to PC filter mats(Millipore), pre-equilibrated with 70% ethanol and water. Plates werewashed thrice with 100 μL 0.8% phosphoric acid and dried for an hour at60° C. 1004 scintillation fluid was added into each well and readingtaken in Perkin Elmer TOPCOUNT beta counter. The data analysis wasperformed by averaging the duplicate top count readings for eachstandard, negative, positive control (enzyme control) and samples andsubtracting the average negative control from each reading which resultsin corrected values. A validation EC₅₀ curve was generated by plottingCPM for each Staurosporine concentration on y-axis against the Logconcentration of Staurosporine (nM) on the x-axis followed by a best fitcurve through the points.

% Inhibition=((Enzyme Control−Compound Treated)/Enzyme Control)×100

Coefficient of Variance (% CV) between replicates: The % CV valuesbetween the replicates were mostly within the acceptable limits of aradiometric experiment. Z′ factor evaluation: The value of Z′ factor wasfound to be 0.8 for SIK2 (SEQ ID NO: 11) and 0.9 was derived for others.

All the compounds were tested in 10-dose IC₅₀ mode with 3 fold serialdilution starting at 100 μM. The control compound Staurosporine wastested in 10 dose IC₅₀ with 3 fold serial dilution starting at 20 μM.The reactions were carried out at 10 μM ATP for SIK2 (SEQ ID NO: 11) andthe results shown in Figure. 1. Referring to FIG. 1, SIK2 (SEQ ID NO:11) inhibitor examples: Panel A: 135 (▪), 142 (A) and Palel B: 133 (▪)and 168 (Δ).

General Protein Kinase Assay Methodology Employed for Selected Kinases

In vitro profiling of the 337 member kinase panel was performed atReaction Biology Corporation using the “HotSpot” assay platform.Briefly, specific kinase/substrate pairs along with required cofactorswere prepared in reaction buffer; 20 mM Hepes (pH 7.5), 10 mMmgCl2, 1 mMEGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO.Compounds were delivered into the reaction, followed ˜20 min later byaddition of a mixture of ATP (Sigma) and 33P ATP (PerkinElmer) to afinal concentration of 10 μM. Reactions were carried out at 25° C. for120 min, followed by spotting of the reactions onto P81 ion exchangefilter paper (Whatman). Unbound phosphate was removed by extensivewashing of filters in 0.75% phosphoric acid. After subtraction ofbackground derived from control reactions containing inactive enzyme,kinase activity data were expressed as the percent remaining kinaseactivity in test samples compared to vehicle (dimethyl sulfoxide)reactions. IC₅₀ values and curve fits were obtained using Prism(GraphPad Software). Kinome tree representations were prepared usingKinome Mapper(http://www.reactionbiology.com/apps/kinome/mapper/LaunchKinome.htm).

TABLE 4 List of Compounds and Corresponding three isoforms of SIKfamily* SIK2 SIK3 (QIK) SIK1 (QSK) (SEQ ID (SEQ ID (SEQ ID EX. NO: 11)NO: 10) NO: 24) 1 ** * * 2 ** * * 5 ** * *** 6 ** ** * 7 ** ND ND 17 **** ** 20 * ND ND 22 * ND ND 23 ** ND ND 24 ** ND ND 25 * ND ND 26 ** NDND 28 ** ND ND 29 ** ND ND 30 * ND ND 36 ** ** ND 37 ** ** ND 47 ** NDND 87 ** * ND 94 * ND ND 95 * * * 96 * * * 97 * * * 98 * * * 99 * ND ND100 * ND ND 101 ** ND ND 113 ** ND ND 114 *** ** * 115 *** ** * 116** * * 120 *** ** ** 123 ** ** ** 124 ** ** ** 125 *** * ND 126 * ND ND128 *** ** ** 132 ** ND ND 133 *** * ** 134 ** ** * 135 *** ** ** 136*** ** ** 137 ** ND ND 138 *** ** ** 139 * ND ND 140 * ND ND 141 *** *** 142 *** * *** 168 *** * * 174 *** * ** 175 *** * ** 176 *** * ** 177*** * ** 178 *** * ** 179 *** * ** 180 *** * ** 181 *** * ** 182 *** *** 183 *** * ** 184 *** * ** 185 *** * ** 191 *** ** ** 192 *** ** **193 *** ** ** 196 *** ** *** 197 *** ** *** 198 *** ** *** 199 *** ** **200 *** ** *** 201 * * * 202 *** ** *** 203 *** * * 204 *** ** *** 205*** ** *** 206 *** ** *** 207 *** ** *** 208 *** ** *** 209 *** *** ***210 *** ** *** 211 *** ** *** 212 *** ** *** 213 *** ** *** 214 ** * **215 ** * ** 216 ** * ** 217 *** ** *** 218 *** ** *** 219 *** ** *** 220** * * 221 * * * 222 * * * 223 * * * 224 *** ** *** 225 *** ** *** 226*** ** *** 227 *** ** *** 228 ND ND ND *Kinase Inhibition Result forSelected Compounds ***<0.1 μM, ** >0.1 μM, * >1 μM ND = Not Determined

Protein Kinase Selectivity Profiler

Selected compounds were tested against 299 protein kinases+17 additionalpreview kinases in single dose duplicate mode at a concentration of 1μM). A control compound was tested in 10-dose IC₅₀ mode with 3-foldserial dilution starting at 20 μM. Reactions were carried out at 10 μMATP. Data pages include raw data, % Enzyme activity (relative to DMSOcontrols), and curve fits.

Cell Culture Models of Cancer Determining 50% Inhibition Concentration(IC₅₀) of 3 Compounds on 2 Human Tumor Cell Lines

CellTiter-Glo (CTG) (Product No.: G7572, Promega. Store CellTiter-Globuffer and CellTiter-Glo substrate at −20° C.), the following protocolis recommended for the preparation of CTG reagent. Thaw theCellTiter-Glo Buffer, and equilibrate to rt prior to use. Forconvenience the CellTiter-Glo buffer may be thawed and stored at rt forup to 48 hr prior to use. Equilibrate the lyophilized CellTiter-Glosubstrate to rt prior to use. Transfer 100 mL of CellTiter-Glo bufferinto the amber bottle containing CellTiter-Glo substrate to reconstitutethe lyophilized enzyme/substrate mixture. This forms the CellTiter-Gloreagent. Mix by gently vortexing, swirling or inverting the contents toobtain a homogeneous solution. The CellTiter-Glo substrate should gointo solution easily in less than 1 minute. Aliquot and store the CTGreagent at −20° C. freezer for long term storage.

Cytotoxicity and IC₅₀ Determination

Day 1: The cells will be harvested during the logarithmic growth periodand counted with hemocytometer. The cell viability should be over 98% bytrypan blue exclusion. Adjust cell solution to the appropriateconcentration with respective medium according the seeding density. Add90 μl cell suspensions to 96-well plates; the final cell seeding densityis 5×10³ cells/90 μl/well for OVCAR-3, 5×10³ cells/90 μl/well forSK-OV-3. Incubate the assay plate for 24 hours at 37° C. in ahumidified, 5% CO₂ atmosphere. Day 2: Prepare serial solution of testarticles with DMSO then dilute with PBS to prepare 10× injectionsolution. Prepare 10× positive drug injection solution with PBS (seeappendix 1). Dispense 104 drug injection solution in each well. Theplates will be cultured for another 72 h, and then measured by means ofMTS assay or CTG assay. Day 5: Thaw the MTS Solution and the PMSSolution, just before addition to the culture plate containing cells,mix PMS Solution with MTS Solution at 1:20 ratio immediately, the finalvolume was based on the actual requirement. Gently swirl the tube toensure complete mixing of the combined MTS/PMS solution. Pipet 204, ofthe combined MTS/PMS solution into the assay wells in one 96 well plate.Incubate the plate for 1-4 h at 37° C. in a humidified, 5% CO₂atmosphere, record the absorbance at 490 nm using SpectraMax. Thaw CTGreagent and equilibrate to rt, pipet 254, to the assay wells in another96 well plate, shake for 2 min with the plate shaker, and incubate for10 min at dark place, then record luminescence reading using Envision.

Data Analysis

The data will be displayed graphically using GraphPad Prism 5.0software. In order to calculate IC₅₀, a dose-responsive curve will befitted using nonlinear regression model with a sigmoidal dose response.The IC₅₀ will be automatically produced by GraphPad Prism 5.0. FIG. 2displays two such plots of SIK2 (SEQ ID NO: 11) inhibitor (191, 206)examples tested in SK-OV-3 and OVCAR3 cell lines with Cisplatin ascontrol. The SK-OV-3 is on the left and the OVCAR3 is on the right.

Survival rate is calculated with the formula ofValue_(sample)/Value_(vehicle control)*100% for CTG assay, andcalculated with the formula of(Value_(sample)−Value_(blank control))/(Value_(vehicle control)−Value_(blank control))*100%

Effects of the Test Compounds on the SIK2-Expressed SKOv3, OVCAR3, ES-2and HEY Cells

Test compound at various concentrations are added in duplicate and thecells were incubated for 72 h. After incubation, CellTiter-Glo® Reagentare added to each test well and mixed for 2 min on an orbital shaker.The plates are shortly centrifuged and incubated at rt for additional 10min to stabilize the luminescent signal and the luminescence signals arerecorded on Pherastar Plus. The cell viability after 72 h compoundtreatment was assayed. 1H-Pyrrolo[2, 3-b]pyridine and1H-Pyrazolo[3,4-b]pyridine series of compounds and its analogues weretested on panel of ovarian cancer cell lines where1H-Pyrazolo[3,4-b]pyridine series inhibited SKOv3 (1.2 μM), OVCAR-3 (0.7μM), HEY 0.07 μM), ES-2 (1.2 μM) (FIGS. 2 b 1-3) and COV434, COV504,EFO-27, HO-8910, OV56, OV90, OVCAR-4, OVISE, OVSAHO, OVTOKO, SW626,TOV-112D and TOV-21G cells inhibited by 1H-Pyrazolo[3, 4-b]pyridineseries with an IC₅₀ between 0.5 to 3.0 μM.

Functional Kinase Assay and the Onset of SIK2 Inhibition:

The functional assays was conducted in order to examine thephosphorylation of SIK2 (SEQ ID NO: 11) at Thr175 that is required forkinase activity and downstream targets on treatment with 1H-Pyrrolo[2,3-b]pyridine and 1H-Pyrazolo[3,4-b]pyridine derivatives. In SKOv3,OVCAR-3, HEY cells the inhibition of phosphorylation of SIK2 (SEQ ID NO:11) at Thr175 and Ser186 monitored after the 1 h treatment with1H-Pyrrolo[2,3-b]pyridine and 1H-Pyrazolo[3,4-b]pyridine derivatives.The treatment with 1H-Pyrrolo[2,3-b]pyridine and1H-Pyrazolo[3,4-b]pyridine derivatives results in inhibition of SIK2(SEQ ID NO: 11) kinase activity will examined from ovarian cancer celllines by western blot. Levels of phospho-SIK2 relative to total-SIK2upon exposure to 1H-Pyrrolo[2,3-b]pyridine and1H-Pyrazolo[3,4-b]pyridine derivatives was determined. The experimentaldetails involves 10 thousand SKOV3ip ovarian carcinoma cells plated in 6cm plates and will be allowed to adhere overnight. All plates treatedwith demecolcine for 6 h, cells were collected released in to new mediacontaining 1H-Pyrrolo[2,3-b]pyridine and 1H-Pyrazolo[3,4-b]pyridinederivatives at 1 h at rt. The cell lysates will be used in Western blotanalysis.

Effects of 1H-Pyrrolo[2,3-b]pyridine and 1H-Pyrazolo[3,4-b]pyridinederivatives on ovarian carcinoma proliferation and apoptosis: As a partof cellular efficacy and possible mechanisms causing the tumor growthinhibition evidenced in the 1H-Pyrrolo[2,3-b]pyridine and1H-Pyrazolo[3,4-b]pyridine derivatives experiments, we further examinedthe effects on tumor cell proliferation by calculating the proliferativeindex after immunohistochemistry on tumors collected at necropsy fromall efficacy experiments. In the SKOv3 model, the proliferation indexfor animals treated with vehicle, 1H-Pyrrolo[2, 3-b]pyridine and1H-Pyrazolo[3,4-b]pyridine derivatives alone and in combination withpaclitaxel and monitor the proliferative indices. Further to gainadditional insight into downstream effects of 1H-Pyrrolo[2,3-b]pyridineand 1H-Pyrazolo[3,4-b]pyridine derivatives, we will conduct theexpression profile studies on SKOv3, OVCAR-3, HEY tumors harvested fromeither vehicle- or 1H-Pyrrolo[2,3-b]pyridine and1H-Pyrazolo[3,4-b]pyridine derivatives treated animals.

In Vivo Models of SIK2 (SEQ ID NO: 11)

SKOV3 ovarian cancer cells injected sub-cutaneous into 32 female nu/numice of approximately and four groups of 8 mice observed with twiceweekly measurements and weekly weights. Treatment with SIK2 (SEQ ID NO:11) inhibitors when progressive growth is observed at 7-14 days. Inseparate experiments, each of two SIK2 (SEQ ID NO: 11) inhibitors1H-Pyrrolo[2,3-b]pyridine derivatives delivered daily by gavage in 3different concentrations (20, 40 and 80 mg/kg) in a volume of 2 mL.Vehicle will be administered for 4th group by gavage. When the controlxenografts have grown to 1.5 cm in diameter, all mice will besacrificed, tumors weighed and tumor tissue cryopreserved and fixed forroutine and EM studies and the duration of time required ˜4 to 6 weeks.The 1H-Pyrrolo[2,3-b]pyridine compounds had significant antitumoreffects as a single agent over combination with taxol.

Efficacy of 1H-Pyrrolo[2,3-b]Pyridine Derivatives in Nu/Nu SKOv3Xenograft Mice:

We examined the growth-inhibitory effect of 1H-Pyrrolo[2,3-b]pyridinederivatives in-vivo employing an i.p. xenograft model in which nu/numice were inoculated i.p. with sensitive cell line SKOv3 cells. One weekafter inoculation, mice were randomized into six treatment groupsreceiving vehicle, 1H-Pyrrolo[2,3-b]pyridine derivatives 30, 60 mg/kg,taxol 10 mg/kg and 1H-Pyrrolo[2,3-b]pyridine plus taxol. Drug treatmentwas well tolerated except i.p. treatment second group, with no apparenttoxicity throughout the study. At the end of an experiment, all micewere sacrificed for tumor volume, weight and each mouse examined andrecorded at autopsy. The two 1H-Pyrrolo[2,3-b]pyridine compounds andtaxol groups all inhibited the abdominal tumor growth and tumor celldissemination (reduced tumor numbers) (FIG. 5a-c ). Taken together,these findings indicates that two 1H-Pyrrolo[2,3-b]pyridine compounds,taxol had significant antitumor effects and compound as a single agentwith the ability not only to inhibit ovarian tumor growth, but alsoinhibits dissemination of tumor cells in vivo.

The Effect of 1H-Pyrrolo[2,3-b]Pyridine Compounds on SKOv3 InducedOrthotopic Murine Model:

Dose-finding experiments initiated by injecting SKOV3ip1 (SKOV3ip1 cellswere collected from cultures using either 0.25% trypsin-EDTA (LifeTechnologies) on the cell line) tumor cells i.p. (2.5×10⁵) into athymicfemale mice. 19 days after tumor cell orthotopic inoculation and wheni.p. tumors were palpable, then the mice randomized into 6 dosagegroups: 0 mg (vehicle alone, group 1), 20 and 40 mg/kg (groups 2, 3)received 1H-Pyrrolo[2,3-b]pyridine compound i.p QD for 3 days (M/W/F),60 and 80 mg/kg (groups 4, 5) received 1H-Pyrrolo[2,3-b]pyridinecompound p.o BID for 3 days (M/W/F) and 100 mg/kg group received1H-Pyrrolo[2,3-b]pyridine compound+Taxol p.o BID for 3 days (M/W/F). BID(twice daily doses) of inhibitor or vehicle were administered by p.o 12h apart and the treatment continued until the vehicle-treated animalsshowed significant tumor burden (for a total of 4 to 6 weeks) andterminate the study at the end of 4 or 6^(th) week and sacrifice animals(mice were sacrificed at 24, 48, and 72 h after the final i.p/p.o) andtumors were harvested for tumor growth inhibition percent andimmunohistochemistry to see the effect of each animal in the group andall tumor nodules were collected, counted, and weighed at necropsy. Inorder to establish the optimal dose and frequency of dosing toeffectively inhibit SIK2 (SEQ ID NO: 11) in-vivo, these dose-findingexperimental samples from orthotopic murine models and using functionalassay we at first investigated the SIK2 (SEQ ID NO: 11) expressionprofiling in control group mice and inhibition of phosphorylation ofSIK2 by 1H-Pyrrolo[2,3-b]pyridine compound and Taxol. Additionally, weperformed quantitative RT-PCR, Western blot, and immunocytologyexperiments to identify overexpression of SIK2 in control groups againsttreatment groups along with SIK2 inhibition of transcription factor CREBvia phosphorylation of its cofactor TORC2/CRTC2 as a biologicalindicator of SIK2 kinase activity. Further characterized the effects ofSIK2 kinase inhibition on tumor growth inhibition, examined the tumornodule formation. 1H-Pyrrolo[2,3-b]pyridine compound, taxol hadsignificant antitumor effects and compound as a single agent, with theability not only to inhibit ovarian tumor growth, but also inhibitsdissemination of tumor cells in vivo.

The Effect of 1H-Pyrrolo[2,3-b]Pyridine Compound on OVCAR-3 InducedOrthotopic Murine Model:

Dose-finding experiments initiated by injecting OVCAR-3 (OVCAR-3 cellswere collected from cultures using either 0.1% EDTA (Life Technologies)on the cell line) tumor cells i.p. (2.5×10⁵) into athymic female mice.Similar study design protocols and analysis performed as described underSKOv3 orthotopic murine experiments.

PHARMACOKINETIC S/ADME/Tox:

The objective of this study was to investigate the bio-availability andpharmacokinetics of a 1H-Pyrrolo[2,3-b]pyridine compound in male SpragueDawley rats. A total of 6 male rats were used in the study. The studywas performed using parallel design (n=3) with serial sampling, assummarized in the Table 5:

TABLE 5 Dose No. Dose volume Strength Route Group # of rats (mg/kg)(mL/kg) (mg/mL) IV ^(a) 1 3 5 2.5 2 PO ^(b) 2 3 20 10 2 ^(a) Ethylalcohol (5% v/v), Polyethylene glycol-300 (50% v/v), Propylene glycol(20% v/v) and water for injection q.s. ^(b) Ethyl alcohol (5% v/v),Polyethylene glycol-300 (50% v/v), Propylene glycol (20% v/v) andMilli-Q ® water q.s. 1H-Pyrrolo [2, 3-b] pyridine compound is orallybioavailable with %F is >20, T_(max) (h) is 6 and T_(1/2) (h) is 5.

1H-Pyrrolo[2,3-b]pyridine compound had solubility at pH 3 is 380 μg/mL,in SGF/SIF its stability is over 120 min (half-life), P-gp substrateclassification is negative. It has no hERG inhibition (IC₅₀>10 μM) andthe P450 IC₅₀ for 1A2, 2C19, 2C9, 2D6>10 μM. 1H-Pyrrolo[2,3-b]pyridinecompound hepatocytes clearance is 9.12 (CL_(int) mL/min/g liver) and inmicrosomes is 8 (CL_(int) mL/min/g liver).

Dose formulations were prepared on the day of doing. Blood samples werecollected at 0.083 (only IV), 0.25, 0.5, 1, 2, 4, 8 and 24 h post-dose.At each time point, approximately 0.2 mL of blood was withdrawn fromeach cannulated rat through jugular vein and transferred to apre-labeled microfuge tube containing 20 μL of 200 mM K₂EDTA permL ofblood. Following collection of blood sample, equal volume of heparinizedsaline was flushed into jugular vein of rat. The blood samples werecentrifuged at 5000 g for 5 minutes at 4±2° C. The plasma was separatedwithin 30 min of scheduled time and stored below −60° C. untilbio-analysis. The plasma samples were analyzed for 114 using a fit-forpurpose liquid chromatographic tandem mass spectrometric detection(LC-MS/MS) method with a lower limit of quantification of 2.21 ng/mL.The pharmacokinetic parameters for compound 114 were calculated usingthe non-compartmental analysis tool of validated WinNonlin® software(Version 5.2).

TABLE 6 Table 6: Rat PK: The pharmacokinetic profiles of test compound114 following intravenous bolus administration and oral gavage in maleSprague Dawley rats. Route T_(max) C_(max) AUC_(last) AUC_(inf) CLV_(ss) T_(1/2) F ^(a) (Dose) (h) (ng/mL) (ng · h/mL) (ng · h/mL)(mL/min/kg) (L/kg) (h) (%) IV NA 3849.91 ^(b) ± 710.44 2599.10 ± 636.932617.38 ± 647.47 33.42 ± 9.57 1.61 ± 0.28 0.54 ± 0.05 — (5 mg/kg) PO0.25 ^(c)   852.56 ± 83.61 1583.84 ± 179.45 1599.77 ± 182.86 NA NA NA 15(20 mg/kg) (0.25-0.5) ^(a) AUC_(inf) and nominal doses were used forbioavailability (% F) calculation; ^(b) concentration at time zero; ^(c)T_(max) is represented as median (range)

Structural Homology Modeling—

Salt Inducible Kinase 2 (SIK2)

The compounds of Formula I, IA and IB provided in Tables 1-3 weredesigned using a structural homology model of SIK2 and its mutant formof SIK2. The homology model of structural model of the kinase domain ofSIK2 was constructed using Salt Inducible Kinase 2 (SIK2) domain regionsequence (11-336) from the full length protein sequence NP_9056006 (FIG.3).

Referring to FIG. 3, Structure based sequence alignment in Clustal W ofthe catalytic protein kinase domains of SIK1 (SNF1LK), SIK2 (SNF1LK,QIK), SIK3 (QSK), AMPK and MARK2. Amino acid residue annotation wereidentical residues (*), highly conserved residues (:), and similarresidues (.) The active site residues highlighted in yellow and thegatekeeper residues in turquoise and the DFG residues shown in yellow.

Sequence search with in the RCSB provided the 2 homologues X-ray crystalstructure templates with ˜52% sequence identity and ˜65% sequencesimilarities was considered as starting point for multiple sequencealignment using Clustal W alignment (FIG. 4) and homology modeling. TheSwiss-Model was applied in sequence alignment, model building, loopprediction and refinement. With the application of FFDD™ (Fragment-FieldDrug Design) workflow design strategy, the final models of SIK2 shown inFigure. 4 were utilized and served as template for designing claimedcompounds. Based on the 3-D profile scoring the structural templatechosen from PDB database and were both MARK2 and AMP-activated proteinkianse (AMPK) crystal structures (PDB ID: 2ROI and 3AQV). Several modelswere built and refined to check the 3D profile and are shown in Figure.4.

Referring to Figure. 4, the homology model of SIK2 in complex with oneof the lead inhibitor is shown. The critical active site residues shownin color-by-atom in stick representations. The inhibitor binding sitedepicted in surface in complex with SIK2. Compound belongs to1H-pyrrolo[2,3-b]pyridine structural class claimed.

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What is claimed is:
 1. A method of inhibiting Salt Inducible Kinase(SIK) activity in a mammal comprising administering to said mammal aneffective amount of a compound of Formula IB:

or a pharmaceutically acceptable salt thereof, wherein: X is N; L¹ isphenyl which is optionally substituted with 1-3 substituents, eachsubstituent independently selected from halo, C₁₋₄alkyl, C₁₋₄alkoxy,trifluoromethyl, trifluoromethoxy, piperazinyl, methylpiperazinyl,

Z is a direct bond, thienyl, thiazolyl, phenyl,

furanyl, piperazinyl, or pyrazolyl; R² is each independently halo, —CN,C₁₋₄alkyl, C₁₋₄alkoxy,

and m is 0, 1, or
 2. 2. The method according to claim 1 wherein thecompound is selected from

or a pharmaceutically acceptable salt thereof.
 3. The method of claim 1,wherein said mammal suffers from a disease selected from cancer or ahyperproliferative disorder.
 4. The method of claim 3, wherein thecancer or hyperproliferative disorder is lung cancer, NSCLC (non smallcell lung cancer), oat-cell cancer, bone cancer, pancreatic cancer, skincancer, dermatofibrosarcoma protuberans, cancer of the head and neck,cutaneous or intraocular melanoma, uterine cancer, ovarian cancer,colorectal cancer, cancer of the anal region, stomach cancer, coloncancer, breast cancer, gynecologic tumor, uterine sarcoma, carcinoma ofthe fallopian tubes, carcinoma of the endometrium, carcinoma of thecervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin'sDisease, hepatocellular cancer, cancer of the esophagus, cancer of thesmall intestine, cancer of the endocrine system, cancer of the thyroidgland, cancer of the parathyroid gland, cancer of the adrenal gland, asarcoma of soft tissue, cancer of the urethra, cancer of the penis,prostate cancer, chronic or acute leukemia, solid childhood tumor,hypereosinophilia, lymphocytic lymphoma, cancer of the bladder, cancerof the kidney or ureter, renal cell carcinoma, carcinoma of the renalpelvis, pediatric malignancy, neoplasm of the central nervous system,primary CNS lymphoma, spinal axis tumor, medulloblastoma, brain stemglioma, pituitary adenoma, Barrett's esophagus, pre-malignant syndrome,neoplastic cutaneous disease, psoriasis, mycoses fungoides, benignprostatic hypertrophy, diabetic retinopathy, retinal ischemia, retinalneovascularization, hepatic cirrhosis, and angiogenesis.
 6. The methodof claim 1 wherein said mammal suffers from ovarian cancer.
 7. Themethod of claim 1 wherein said mammal suffers from a disease selectedfrom stroke, obesity, type II diabetes, cardiovascular disease,atherosclerosis, immunological disease, autoimmune disease, or renaldisease.
 8. The method of claim 2, wherein said mammal suffers from adisease selected from cancer or a hyperproliferative disorder.
 9. Themethod of claim 8, wherein the cancer or hyperproliferative disorder islung cancer, NSCLC (non small cell lung cancer), oat-cell cancer, bonecancer, pancreatic cancer, skin cancer, dermatofibrosarcoma protuberans,cancer of the head and neck, cutaneous or intraocular melanoma, uterinecancer, ovarian cancer, colorectal cancer, cancer of the anal region,stomach cancer, colon cancer, breast cancer, gynecologic tumor, uterinesarcoma, carcinoma of the fallopian tubes, carcinoma of the endometrium,carcinoma of the cervix, carcinoma of the vagina, carcinoma of thevulva, Hodgkin's Disease, hepatocellular cancer, cancer of theesophagus, cancer of the small intestine, cancer of the endocrinesystem, cancer of the thyroid gland, cancer of the parathyroid gland,cancer of the adrenal gland, a sarcoma of soft tissue, cancer of theurethra, cancer of the penis, prostate cancer, chronic or acuteleukemia, solid childhood tumor, hypereosinophilia, lymphocyticlymphoma, cancer of the bladder, cancer of the kidney or ureter, renalcell carcinoma, carcinoma of the renal pelvis, pediatric malignancy,neoplasm of the central nervous system, primary CNS lymphoma, spinalaxis tumor, medulloblastoma, brain stem glioma, pituitary adenoma,Barrett's esophagus, pre-malignant syndrome, neoplastic cutaneousdisease, psoriasis, mycoses fungoides, benign prostatic hypertrophy,diabetic retinopathy, retinal ischemia, retinal neovascularization,hepatic cirrhosis, and angiogenesis.
 10. The method of claim 2 whereinsaid mammal suffers from ovarian cancer.
 11. The method of claim 2wherein said mammal suffers from a disease selected from stroke,obesity, type II diabetes, cardiovascular disease, atherosclerosis,immunological disease, autoimmune disease, or renal disease.